[go: up one dir, main page]

WO2021068961A1 - 一种吸入溶液药物组合物及其制备方法 - Google Patents

一种吸入溶液药物组合物及其制备方法 Download PDF

Info

Publication number
WO2021068961A1
WO2021068961A1 PCT/CN2020/120348 CN2020120348W WO2021068961A1 WO 2021068961 A1 WO2021068961 A1 WO 2021068961A1 CN 2020120348 W CN2020120348 W CN 2020120348W WO 2021068961 A1 WO2021068961 A1 WO 2021068961A1
Authority
WO
WIPO (PCT)
Prior art keywords
indacaterol
pharmaceutical composition
sodium
add
citric acid
Prior art date
Application number
PCT/CN2020/120348
Other languages
English (en)
French (fr)
Inventor
张轩邈
毛华
周洋
邹孟玮
杨必坤
Original Assignee
四川海思科制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川海思科制药有限公司 filed Critical 四川海思科制药有限公司
Priority to CN202210912500.7A priority Critical patent/CN115998680A/zh
Priority to CN202080037401.8A priority patent/CN113853197B/zh
Priority to CN202210936672.8A priority patent/CN115337292A/zh
Publication of WO2021068961A1 publication Critical patent/WO2021068961A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the invention relates to an inhalation solution pharmaceutical composition, in particular to an inhalation solution pharmaceutical composition containing indacaterol, and belongs to the field of pharmaceutical preparations.
  • COPD chronic obstructive pulmonary disease
  • Indacaterol is a new type of long-acting ⁇ 2-receptor agonist (LABA), produced by Novartis Pharmaceuticals, Switzerland. It has been marketed in more than 70 countries and regions around the world since 2009. It was approved by the Chinese National Drug Administration in June 2012. Approved by the Bureau for listing in China, it is China’s first single LABA formulation approved for the treatment of COPD.
  • the only single inhalation preparation of indacaterol currently on the market is Angrun (Indacaterol maleate inhalation powder mist) This kind of powder mist dosage form.
  • the dry powder inhalation method requires the patient to learn the method of inhalation and the patient needs to have good lung function to inhale the drug.
  • CN103860463A discloses a solution containing indacaterol maleate and its inhalation spray.
  • concentration of indacaterol maleate in the published prescription is very low, only 2.0 mcg/mL-15 mcg/mL.
  • the inhalation solution generally requires the atomization time to be controlled within 10 minutes. If the volume of the atomization solution is too large, the atomization time will increase significantly and cannot meet the clinical needs. Generally, the volume of the inhalation solution needs to be controlled within 3 mL.
  • indacaterol maleate inhalation solution drug concentration 15mcg/mL
  • drug concentration 15mcg/mL drug concentration 15mcg/mL
  • the specifications of (indacaterol maleate inhalation powder mist) (150mcg based on indacaterol) remain the same, so the volume of the atomized solution needs to be more than 10mL, which is much higher than the volume of the conventional atomized solution.
  • the concentration of the drug in the indacaterol maleate inhalation solution is too low, which causes the volume of the aerosol solution to be too large and the aerosol inhalation time is too long, which cannot meet the clinical needs.
  • Jerun (Indacaterol inhalation powder mist) is a new type of inhalation preparation for the treatment of COPD.
  • This product is a compound powder mist containing two bronchodilators, of which indacaterol is a long-acting ⁇ 2- Receptor agonist (LABA), glycopyrrolate is a long-acting anticholinergic (LAMA) drug.
  • LABA/LAMA drug As the world's first LABA/LAMA drug on the market, indacaterol glycopyrrolate can agonize ⁇ 2 receptors while blocking M3 receptors. It has a powerful synergistic effect and can significantly improve lung function compared with single-agent therapy. , Bringing better treatment methods for the treatment of COPD.
  • the product has only one dosage form of inhalation powder.
  • inhalation powder For some patients with severe COPD, due to their poor lung function, they may not be able to achieve the inhalation airflow required for inhalation of powder mist, and the drug cannot be effectively delivered to the lungs or delivered doses. Decrease, so that the efficacy of the drug decreases.
  • the use of aerosol inhalation to administer medicine does not require special training for patients, especially for severe COPD patients, who can inhale a sufficient dose of medicine by using normal breathing methods. Therefore, the development of a compound inhalation solution of indacaterol glycopyrronium bromide can well meet the clinical needs of such patients. However, so far there is no research report on indacaterol glycopyrrolate compound inhalation solution.
  • one object of the present invention is to provide a pharmaceutical composition of inhalation solution containing indacaterol or its salt.
  • concentration of the drug in the composition is high enough to meet the clinical requirements for the volume of the inhalation solution. It is required to use manual pump, ultrasonic spray, air compressor and other pressure to release the content in a mist form. It is a preparation for lung inhalation.
  • the high concentration of sodium chloride in the composition can help reduce respiratory tract irritation and keep the droplet size stable.
  • Another object of the present invention is to provide a stable indacaterol compound inhalation solution prescription and preparation method thereof.
  • the drug concentration in the preparation is high and the preparation has good chemical stability, which can meet the clinical requirements well. Demand.
  • a pharmaceutical composition for an inhalation solution which comprises an active ingredient indacaterol or a pharmaceutically acceptable salt thereof, a pH adjusting agent, and water, wherein the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof is the same as the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof. Daterol counts as 23.2mcg/mL ⁇ 231.5mcg/mL, and its pH is 2.0 ⁇ 5.5.
  • the pharmaceutically acceptable salt of the active ingredient indacaterol includes indacaterol maleate or indacaterol acetate.
  • the inhalation solution pharmaceutical composition of the present invention contains 30 mcg to 300 mcg of indacaterol maleate per 1 mL, and has a pH of 3.0 to 4.0.
  • the pH adjusting agent is selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate
  • the pH of the pharmaceutical composition is 2.5-5.0.
  • the pharmaceutical composition further comprises other adjuvants, and the other adjuvants are selected from at least one of a solubilizer, an osmotic pressure regulator, and a buffer ion pair.
  • the solubilizer is selected from at least one of polysorbate, polyethylene glycol castor oil, polyoxyethylene castor oil, and lecithin.
  • the osmotic pressure regulator is selected from at least one of sodium chloride or mannitol.
  • the buffer ion pair is selected from the group consisting of citric acid-sodium citrate buffer pair, disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, sodium bicarbonate-sodium carbonate buffer pair, acetic acid-sodium acetate buffer pair,
  • the tartaric acid-sodium tartrate buffer pair has a concentration of 1 mM-50 mM.
  • the concentration of the buffer ion pair mentioned here is calculated based on the total molar concentration of acid radicals that play a buffering role in the buffer ion pair.
  • a citric acid-sodium citrate buffer pair with a concentration of 6 mM is prepared. It means that the molar concentration of citrate is 6mM, which can be prepared by adding 4mmol of citric acid and 2mmol of sodium citrate to 1000mL of water.
  • the concentration of the buffer ion pair is 3 mM to 30 mM.
  • the citric acid-sodium citrate buffer pair can be prepared with citric acid and sodium hydroxide, and the citric acid used is selected from one or more of anhydrous citric acid and citric acid monohydrate The combination.
  • the citric acid-sodium citrate buffer pair can be prepared with citric acid and sodium citrate, and the citric acid used is selected from one or more of anhydrous citric acid and citric acid monohydrate
  • the sodium citrate used is selected from one or more combinations of anhydrous sodium citrate, sodium citrate dihydrate, and sodium citrate pentahydrate.
  • the pH 4.0 citric acid-sodium citrate buffer pair of the present invention can be prepared from citric acid and sodium citrate in an aqueous solution, wherein the molar ratio of the added amount of citric acid and sodium citrate The ratio is 2:1.
  • a pH 4.0 citric acid-sodium citrate buffer pair with a concentration of 5 mM it can be prepared by adding 3.34 mmol of citric acid and 1.67 mmol of sodium citrate to 1000 mL of water.
  • the pharmaceutical composition further comprises a short-chain alcohol selected from one or a combination of ethanol, propylene glycol, and glycerol.
  • the osmotic pressure regulator when the weight percentage of indacaterol or a pharmaceutically acceptable salt thereof is 23.2mcg/mL ⁇ 77.2mcg/mL based on indacaterol, the osmotic pressure regulator The content is 0.1% to 0.9%.
  • the osmotic pressure regulator when the weight percentage of indacaterol or a pharmaceutically acceptable salt thereof is 77.3mcg/mL ⁇ 231.5mcg/mL, the osmotic pressure regulator The content is 0.1% to 0.7%.
  • the content of the indacaterol maleate is 30 mcg/mL-100 mcg/mL, and the content of the osmotic pressure regulator is 0.3 g/mL- 0.9g/mL.
  • the content of the indacaterol maleate is 100 mcg/mL ⁇ 300 mcg/mL, and the content of the osmotic pressure regulator is 0.3g/mL ⁇ 0.7g/mL.
  • the short-chain alcohol when the short-chain alcohol is ethanol, its weight percentage is 0.02% to 0.08%.
  • the weight ratio of propylene glycol to water is 1:4-200.
  • the weight ratio of glycerol to water is 1:20-200.
  • the pharmaceutical composition further comprises the active ingredients glycopyrrolate, tiotropium bromide, ipratropium bromide, umetopium bromide, adesonium bromide, budesonide, ciclesonide , At least one of beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate, and the concentration of these active ingredients in the pharmaceutical composition is independently 20 mcg/mL to 500 mcg/mL.
  • the pharmaceutical composition further comprises glycopyrrolate, and each 1000 mL of the pharmaceutical composition contains the glycopyrrolate from 0.05 to 0.5 g.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, chlorine 3g ⁇ 7g of sodium, 0.6g ⁇ 2.8g of citric acid monohydrate, 0.4g ⁇ 2.0g of sodium citrate dihydrate, appropriate amount of pH regulator to adjust pH to 2.5 ⁇ 5.0, water to 1000mL.
  • the pharmaceutical composition per 1000 mL contains: 0.108 g indacaterol maleate, 0.058 g glycopyrrolate, 0.699 g citric acid monohydrate, 0.492 g sodium citrate dihydrate, sodium chloride 6g, adjust the pH to 4.0 with a proper amount of pH adjuster, and add water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, 0.04g ⁇ 0.23g, mometasone furoate 0.04g ⁇ 0.5g, chlorine 3g ⁇ 7g of sodium, 0.6g ⁇ 2.8g of citric acid monohydrate, 0.4g ⁇ 2.0g of sodium citrate dihydrate, appropriate amount of pH regulator to adjust pH to 2.5 ⁇ 5.0, water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, and bran Mometasone acid 0.04g ⁇ 0.5g, sodium chloride 3g ⁇ 7g, citric acid monohydrate 0.6g ⁇ 2.8g, sodium citrate dihydrate 0.4g ⁇ 2.0g, pH adjuster appropriate to adjust pH to 2.5 ⁇ 5.0, add water To 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, chlorine Sodium hydroxide 3g ⁇ 7g, citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g ⁇ 4g citric acid monohydrate and 0.1g ⁇ 0.8g sodium hydroxide, pH adjuster, adjust the pH to 2.5 ⁇ 5.0, add water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, 0.04g ⁇ 0.23g, mometasone furoate 0.04g ⁇ 0.5g, chlorine Sodium hydroxide 3g ⁇ 7g, citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g ⁇ 4g citric acid monohydrate and 0.1g ⁇ 0.8g sodium hydroxide, pH adjuster, adjust the pH to 2.5 ⁇ 5.0, add water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, and bran Mometasone acid 0.04g ⁇ 0.5g, sodium chloride 3g ⁇ 7g, citric acid-sodium citrate buffer pair obtained by the reaction of citric acid monohydrate 0.5g ⁇ 4g and sodium hydroxide 0.1g ⁇ 0.8g, pH adjuster appropriate amount Adjust the pH to 2.5 ⁇ 5.0, and add water to 1000mL.
  • the aforementioned pH adjusting agent is selected from one of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate or disodium hydrogen phosphate Or multiple.
  • the citric acid-sodium citrate buffer pair of the present invention is prepared from citric acid and sodium citrate in an aqueous solution.
  • This buffer pair can also be prepared in other ways, such as using citric acid and sodium hydroxide in an aqueous solution, or using sodium citrate and hydrochloric acid in an aqueous solution.
  • the mcg is the mass unit microgram, that is, ⁇ g.
  • the citric acid used in the present invention is all citric acid monohydrate.
  • the use of anhydrous citric acid or other types of citric acid hydrates can also achieve the same technical effect as the use of citric acid monohydrate, which also belongs to the scope of the present invention.
  • the sodium citrate used in the present invention is all sodium citrate dihydrate.
  • the use of anhydrous sodium citrate or other types of sodium citrate hydrate such as sodium citrate pentahydrate can also achieve the same technical effect as the use of sodium citrate dihydrate, which also belongs to the scope of the present invention.
  • the present invention also provides a preparation method of indacaterol inhalation solution pharmaceutical composition, which comprises the following steps:
  • auxiliary materials are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols. Stir to disperse and dissolve the auxiliary materials and adjust the pH of the solution to Target value 2.0 ⁇ 5.5;
  • filter sterilization of the drug solution obtained in (b) above for example, filter sterilization with a filter membrane less than or equal to 0.22 ⁇ m to obtain a sterile drug solution.
  • sterile budesonide a compound selected from the group consisting of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, and fluticasone furoate to the sterile drug solution, and stir Disperse evenly.
  • the obtained sterile pharmaceutical solution is divided into a vial, a glass ampoule or a plastic ampoule, for example, to obtain the indacaterol inhalation solution pharmaceutical composition.
  • the present invention provides a preparation method of indacaterol inhalation solution pharmaceutical composition, the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution.
  • the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution.
  • the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution.
  • the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the pharmaceutical composition of indacaterol inhalation solution provided by the present invention overcomes the shortcomings of the existing indacaterol inhalation solution that the concentration is low and cannot be used clinically, and a higher concentration of sodium chloride can be added to the prescription while maintaining indacaterol.
  • the high concentration of indacaterol greatly increases the concentration of indacaterol in the inhalation solution preparation, and smoothly realizes the preparation of large-scale preparations of indacaterol inhalation solution preparations. This high-concentration indacaterol inhalation solution is better Meet the clinical needs.
  • the indacaterol glycopyrrolate compound inhalation solution composition provided by the present invention is the first report.
  • the drug concentration in the preparation is high and the preparation has good chemical stability, which can well meet the clinical needs; on the other hand,
  • the difference in FPF value of the inhalation solution of the present invention at different air flow rates is small (the dry powder inhalation preparation is larger), and it can be applied to patients with different inhalation capabilities (the dry powder inhalation preparation is not suitable for patients with weak inhalation ability), which improves The patient's medication compliance.
  • Test Examples 1-8 Study the solubility of indacaterol maleate in different pH solutions
  • Preparation method Measure 1000mL of water, add appropriate amount of hydrochloric acid to adjust the pH to the pH value stated in the prescription, the error range does not exceed ⁇ 0.05, then add 0.5g of indacaterol maleate raw material, stir at 25°C for 24 hours, and filter After testing the sample concentration.
  • test results show that in a solution with a pH of 2.0 to 5.5, about 100 to 300 mcg of indacaterol maleate can be dissolved per 1 ml, and the solubility of indacaterol maleate is higher in a low pH solution.
  • Test Examples 9-14 To study the stability of indacaterol solution under different pH conditions.
  • Test Example 9 Test Example 10 Test Example 11 Test Example 12 Test Example 13 Test Example 14 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g pH 3.0 3.5 4.0 4.5 5.0 5.5 Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water separately, adjust the pH of the solution to the pH value stated in the prescription with an appropriate amount of hydrochloric acid, and the error range does not exceed ⁇ 0.05, and then add 0.15g of indacaterol maleate raw material, stir overnight, and filter Fill them in ampoules and place them at 4°C and 25°C, and check the relevant substances in the samples in January, 2 and March.
  • test results show that under the condition of 4° C., the impurity amount of Test Example 9-14 has no obvious change compared with that of 0 days, and at the same time, the impurity amount of Test Example 9-14 has increased with the increase of temperature.
  • the inventor also found that in a solution with a pH of 5.0 to 5.5, the amount of impurities exceeded 1% for 3 months at 25°C. Therefore, in a pH 3.0-4.5 solution, indacaterol maleate is more stable at 25°C.
  • Test Examples 15-18 To investigate the solubility of indacaterol maleate in different pH solutions when stored at low temperature
  • Test Example 15 Test Example 16 Test Example 17 Test Example 18 Indacaterol maleate 0.3g 0.3g 0.3g 0.3g hydrochloric acid Right amount / / / Citric acid-sodium citrate buffer pair / 5mM 5mM 5mM pH 3.0 4.0 4.5 5.0 Add water to 1000mL 1000mL 1000mL 1000mL
  • Test Example 16-18 add 0.699g of citric acid and 0.492g of sodium citrate, stir and dissolve, adjust the pH to the prescribed pH, the error range is not If it exceeds ⁇ 0.05, add 0.3g of indacaterol maleate, stir overnight, filter and dispense into ampoules, store in a refrigerator at 2-8°C, test the concentration and pH of the sample at 0 time and 72 hours respectively . Before the concentration test, the sample in the ampoule needs to be filtered to remove undissolved drug particles. The test results are:
  • an osmotic pressure regulator needs to be added, and sodium chloride is commonly used to adjust the osmotic pressure of the solution.
  • sodium chloride is commonly used to adjust the osmotic pressure of the solution.
  • the present invention found in the research that sodium chloride will affect the solubility of indacaterol maleate, so it is necessary to investigate the effect of different concentrations of sodium chloride on the solubility of indacaterol maleate.
  • Test Examples 19-27 Investigate the influence of sodium chloride concentration on the solubility of indacaterol maleate
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in test examples 19-21; add 1.398 g of citric acid and 0.984 g of sodium citrate in test examples 22-24; add citric acid in test examples 25-27 2.796g, 1.968g sodium citrate, stir until completely dissolved, then add the corresponding sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add 0.3g of indacaterol maleate raw material , Stir overnight, filter and dispense into ampoules. Test the concentration and pH of the chemical solution. At the same time, they were placed in a refrigerator at 2-8°C for 3 days and 7 days respectively to determine the concentration and pH of the sample. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • test results are:
  • the present invention finds that the citric acid-sodium citrate buffer pair can improve the solubility of indacaterol maleate in a solution containing sodium chloride, and reduce the risk of drug precipitation during storage.
  • citric acid-sodium citrate buffer In order to clarify the concentration of citric acid-sodium citrate buffer in the solution, it is necessary to study the influence of different concentrations of citric acid-sodium citrate buffer on the solubility of indacaterol maleate in sodium chloride solution.
  • Test Examples 28-32 Investigate the effect of citric acid-sodium citrate buffer on the solubility of indacaterol maleate in sodium chloride solution
  • Test Example 32 Indacaterol maleate 0.2g 0.2g 0.2g 0.2g 0.2g 0.2g Citric acid-sodium citrate buffer pair - 5mM 20mM 30mM 50mM Sodium chloride 6g 6g 6g 6g 6g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add citric acid 0.699 g, 1.398 g, 4.194 g, 6.990 g, and sodium citrate 0.492 g, 1.968 g, 2.952 g, 4.920 g, respectively, in Test Examples 29-32, and stir until completely dissolved.
  • Test examples 28 to 32 were then added 6g of sodium chloride and stirred until completely dissolved; added appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, and then added 0.2g of indacaterol maleate raw material, stirred overnight, filtered and then packed Test the concentration and pH of the sample in an ampoule. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles. At the same time, they were placed in a refrigerator at 2-8°C for 7 days and then tested again. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • test results are:
  • the citric acid-sodium citrate buffer pair can increase the solubility of indacaterol maleate in sodium chloride solution, and can reduce the indacaterol maleate during storage. The risk of precipitation.
  • Test Example 33 To investigate whether a high-concentration and stable indacaterol maleate solution can be prepared according to the prescription of Example 1 in patent CN103860463A.
  • Test Example 34 To investigate whether a high-concentration and stable indacaterol maleate solution can be prepared according to the prescription of Example 3 in patent CN103860463A
  • Indacaterol maleate 0.02g Disodium phosphate 2g Dipotassium phosphate 7.5g Sodium chloride 0.5g Sodium formaldehyde sulfoxylate 22.5mg Ethylenediaminetetraacetic acid monocalcium disodium 50mg water 1000mL
  • Preparation method Measure 1000mL of water and add 0.1g of polysorbate-80 to dissolve it, adjust the pH to the prescribed pH with hydrochloric acid, and the error range does not exceed ⁇ 0.05, and then add the corresponding amount of indacaterol maleate. Stir and dissolve at room temperature, filter and fill in an ampoule to detect the sample concentration and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • Example 1 77.41 0.133
  • Example 2 229.76 0.138
  • Example 3 76.64 0.129
  • Example 4 231.07 0.117
  • Example 5 78.87 0.122
  • Example 6 230.23 0.123
  • Example 7 76.95 0.163
  • Example 8 228.98 0.149
  • Example 10 Indacaterol maleate 0.2g 0.2g 0.2g Polyethylene Glycol Castor Oil / / 1g Lecithin / 1g / Polyoxyethylene castor oil 0.4g / / pH 4.0 4.0 4.0 Add water to 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add corresponding amounts of polyethylene glycol castor oil, lecithin, and polyoxyethylene castor oil according to the above-mentioned examples. After it is completely dissolved, adjust the pH to 4.0 ⁇ 0.05 with hydrochloric acid, and then add Malay 0.2g of indacaterol acid was stirred and dissolved at room temperature, filtered and filled in an ampoule to detect the concentration of the sample and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • Example 9 154.20 0.132
  • Example 10 159.29 0.121
  • Example 11 155.59 0.133
  • Example 13 Indacaterol maleate 0.05g 0.05g sulfuric acid Right amount / Lysine / Right amount pH 4.0 4.0 Add water to 1000mL 1000mL
  • Preparation method Measure 1000mL of water, adjust the pH to 4.0 ⁇ 0.05 with sulfuric acid or lysine respectively, add 0.05g of indacaterol maleate drug, stir and dissolve at room temperature, filter and fill in an ampoule. Detect sample concentration and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid, 0.492g of sodium citrate, stir until completely dissolved, then add 6g of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add the corresponding Ethanol, propylene glycol, and glycerol, stir to make the mixture uniform. Measure 1000 mL of the corresponding solution, add 0.15 g of indacaterol maleate, stir overnight, filter, and divide the solution to test the content and pH value. Test the concentration and pH value after 3 days and 7 days in the refrigerator at 2-8°C. Before the concentration test, the sample needs to be filtered to remove possible precipitated drug particles.
  • Example 21 Example 22
  • Example 23 Example 24 Indacaterol maleate 0.05g 0.1g 0.1g 0.25g 0.15g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 20mM 20mM Sodium chloride 3g 6g 9g 3g 6g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate in Examples 20-22; add 2.796g of citric acid and 1.968g of sodium citrate in Examples 23-24, stir until completely dissolved, add the corresponding After the amount of sodium chloride is completely dissolved, adjust the pH to 4.00 ⁇ 0.05 with hydrochloric acid, and then add the corresponding amount of indacaterol maleate drug, stir overnight, filter, and distribute, and test the concentration and related substances. Before the concentration test, the sample needs to be filtered to remove possible precipitated drug particles.
  • Example 20 38.94 0.127
  • Example 21 80.03 0.132
  • Example 22 78.18 0.137
  • Example 23 193.33 0.112
  • Example 24 115.42 0.125
  • Example 25 Example 26
  • Example 27 Example 28 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM Sodium chloride 3g 4g 5g 6g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid, 0.492g of sodium citrate, dissolve, add the prescribed amount of sodium chloride, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with appropriate amount of hydrochloric acid, and finally add inda maleate Terol drug is 0.15g, stirred overnight, filtered and then divided into aliquots to test the concentration and related substances. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 25 116.00 0.142
  • Example 26 119.35 0.133
  • Example 27 114.84 0.152
  • Example 28 115.53 0.139
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate in Examples 29 to 31; add 4.194g of citric acid and 2.952g of sodium citrate in Examples 32 to 34, stir until completely dissolved, add 6g respectively Sodium chloride, after it is completely dissolved, adjust the pH to 4.00 ⁇ 0.05 with hydrochloric acid, then add the corresponding amount of indacaterol maleate and glycopyrrolate, stir overnight, filter and dispense, test the concentration, related substances and pH value. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 36 Indacaterol maleate 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.2g 0.2g Polysorbate-80 / / 0.05g Citric acid-sodium citrate buffer pair 20mM 20mM 20mM Sodium chloride 3g 3g 3g hydrochloric acid Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 2.796g of citric acid and 1.968g of sodium citrate, stir until completely dissolved, then add sodium chloride and polysorbate-80, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add 0.15g of indacaterol maleate and glycopyrrolate, stir to dissolve, filter and dispense into ampoules to test the concentration of the two drugs and related substances. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 24 and Examples 35 to 37 were placed in a thermostat at 5 ⁇ 2° C. to investigate the changes in related substances and pH values of the samples during the placement process.
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid, 0.492 g of sodium citrate, and 5 g of sodium chloride in Examples 41 to 43, stir until completely dissolved, adjust the pH to the corresponding pH with hydrochloric acid, and the error range does not exceed ⁇ 0.05; For Examples 38-40, add 5g of sodium chloride, stir and dissolve, adjust the pH to the corresponding pH with hydrochloric acid, and the error range does not exceed ⁇ 0.05. Finally, each example is added with the prescribed amount of medicine, stirred and dissolved, filtered, and packed into ampoules. In, test the concentration separately. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 38 116.23 100.32
  • Example 39 115.53 100.74
  • Example 40 115.19 202.42
  • Example 41 117.15 99.81
  • Example 42 116.11 204.20
  • Example 43 115.53 100.84
  • test results show that in a solution containing 0.5% sodium chloride and a pH of 2 to 5, an inhalation solution with a suitable concentration can be prepared.
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate, stir until completely dissolved, then add the prescribed amount of sodium chloride, and stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then Add 0.15 g of indacaterol acetate or indacaterol and the prescription amount of glycopyrrolate crude drug, stir until completely dissolved, and test the concentration after filtration. Before the concentration test, the undissolved drug needs to be filtered out.
  • test results show that both indacaterol acetate or indacaterol can be combined with glycopyrrolate to prepare a compound inhalation solution.
  • Example 51 Example 52
  • Example 53 Indacaterol 0.15g 0.15g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g / / / Tiotropium Bromide / 0.1g / / Ipratropium bromide / / 0.1g / Umetium Bromide / / / 0.1g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM Sodium chloride 3g 3g 3g 3g 3g 3g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate, stir until completely dissolved, then add 3g of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add The prescription amount of the medicine as shown in the above table is stirred until it is completely dissolved, filtered and then divided into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 54 to 57, stir until completely dissolved, then add the prescribed amount of sodium chloride, stir until completely dissolved, add an appropriate amount of hydrochloric acid to adjust the pH To 4.00 ⁇ 0.05;
  • Examples 58-59 add the prescription amount of sodium chloride, stir to dissolve, add appropriate amount of hydrochloric acid to adjust the pH to 3.00 ⁇ 0.05; All the examples add indacaterol maleate and glycopyrrolate according to the prescriptions , After stirring overnight for the drug to dissolve, add mometasone furoate or fluticasone propionate, stir evenly, and dispense into ampoules to test the concentration.
  • the test results are as follows:
  • Preparation method Measure 1000mL of water, add prescription amount of citric acid and sodium citrate, stir until completely dissolved, then add prescription amount of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add to the table
  • the prescription amount of indacaterol acetate and glycopyrronium bromide shown in stir overnight until the raw material is completely dissolved, then add the prescription amount of mometasone furoate or fluticasone propionate or fluticasone furoate, stir well, and dispense into ampoules In the bottle, test the concentration separately.
  • the test results are as follows:
  • test results show that indacaterol acetate and glycopyrrolate can be combined with different steroid hormones to prepare a ternary compound inhalation solution.
  • Preparation method Measure 1000mL of water, add the prescribed amount of buffer salt, stir until completely dissolved, then add 3g of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to the pH set in the table, and then add the prescription
  • the amount of medicine is stirred until it is completely dissolved, filtered and divided into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 66 115.53 100.42
  • Example 67 114.38 102.73
  • Example 68 116.11 202.22
  • Example 69 77.72 299.10
  • Example 70 45.80 399.69
  • Example 71 45.94 51.17
  • Example 76 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair - 5mM 20mM 5mM 5mM Mannitol 50g 50g 50g 25g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Example 73 and Examples 75 to 76, and add 2.796 g of citric acid and 1.968 g of sodium citrate in Example 74. After stirring and dissolving, each Example Add mannitol according to the prescription, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount of indacaterol maleate and glycopyrrolate, stir to dissolve, filter and dispense into ampoules , Respectively test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 72 116.11 100.20
  • Example 73 117.73 100.52
  • Example 74 115.42 103.17
  • Example 75 114.84 99.42
  • Example 76 118.31 100.71
  • test results show that mannitol, as an osmotic pressure regulator, can prepare a compound inhalation solution with a content that meets the requirements.
  • Example 81 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 10mM 20mM Sodium chloride 3g 4g 5g 5g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 77 to 79; add 1.398 g of citric acid and 0.984 g of sodium citrate in Example 80; add 2.796 g of citric acid in Example 81 Sodium citrate 1.968g, after stirring and dissolving, in each example, add sodium chloride according to the prescription, stir and dissolve, adjust the pH to 3.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount of indacaterol maleate and glycopyrrolate. Stir to dissolve, filter and dispense into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 77 116.23 100.23
  • Example 78 117.15 99.83
  • Example 79 115.19 102.90
  • Example 80 115.53 101.45
  • Example 81 116.11 101.27
  • test results show that the pH3.0 solution contains different concentrations of citrate buffer salt, and a binary compound inhalation solution with a content that meets the requirements can be prepared.
  • Example 82 Example 83
  • Example 84 Example 85
  • Example 86 Indacaterol maleate 0.25g 0.05g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.3g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 10mM 40mM Sodium chloride 3g 4g 5g 5g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 82 to 84; add 2.102 g of citric acid and 0.456 g of sodium hydroxide in Example 85; add 8.408 g of citric acid in Example 86.
  • Sodium hydroxide 1.824g after stirring and dissolving, sodium chloride was added in each example according to the prescription, stirring and dissolving, adjusting the pH to 3.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally adding the prescription amount of indacaterol maleate and glycopyrrolate.
  • Example 82 190.13 101.23
  • Example 83 38.90 299.72
  • Example 84 116.00 100.23
  • Example 85 115.49 99.74
  • Example 86 114.43 100.29
  • test results show that in a pH 3.0 solution, a citric acid buffer solution prepared with citric acid and sodium hydroxide can prepare a binary compound inhalation solution with a content that meets the requirements.
  • Example 87 Example 88
  • Example 89 Example 90
  • Example 91 Indacaterol maleate 0.12g 0.12g 0.12g 0.12g 0.12g Glycopyrrolate 0.06g 0.06g 0.06g 0.06g Mometasone furoate / / / 0.15g 0.15g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM 50mM Sodium chloride 4g 5g 6g 4g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 91 Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 87 to 90; add 10.51 g of citric acid and 2.28 g of sodium hydroxide in Example 91.
  • sodium chloride was added in each example according to the prescription, stirred and dissolved, adjusted to pH 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally added the prescription amount of indacaterol maleate and Glycopyrrolate, stir to dissolve.
  • Examples 87-89 were filtered and divided into ampoules, and the concentrations were tested respectively.
  • a prescription amount of mometasone furoate was added after filtration, and mometasone furoate was dispersed by high-speed shearing, and then divided into ampoules to test the concentration.
  • test results show that: in a pH 4.0 solution, a citric acid buffer solution prepared with citric acid and sodium hydroxide can prepare a binary compound inhalation solution and a ternary compound inhalation preparation that meet the requirements.
  • Example 92 Example 93
  • Example 94 Example 95
  • Example 96 Indacaterol maleate 0.12g 0.12g 0.12g 0.12g 0.12g Mometasone furoate 0.5g 0.3g 0.4g 0.15g 0.05g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM 50mM Sodium chloride 4g 5g 6g 4g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 96 Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 92 to 95; add 10.51 g of citric acid and 2.28 g of sodium hydroxide in Example 96.
  • sodium chloride was added in each example according to the prescription, stirred and dissolved, adjusted to pH 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally added the prescription amount of indacaterol maleate.
  • Stir to dissolve add the prescribed amount of mometasone furoate after filtering, disperse mometasone furoate at high speed, and then divide them into ampoules to test the concentration.
  • Example 92 91.72 507.63
  • Example 93 90.56 294.31
  • Example 94 91.16 405.66
  • Example 95 93.25 147.58
  • Example 96 94.67 53.12
  • test results show that in a pH 4.0 solution, a citric acid buffer pair solution prepared by citric acid and sodium hydroxide can prepare indacaterol mometasone furoate binary compound inhalation solution with a content that meets the requirements.
  • Example 97 Example 98 Example 99 Indacaterol maleate 0.005g 0.005 0.12 Disodium phosphate 2g / / Dipotassium phosphate 7.5g / / Sodium chloride 0.5g 4g 4g Sodium formaldehyde sulfoxylate 0.0225g / / Ethylenediaminetetraacetic acid-calcium disodium 0.05g / / Citric acid-sodium citrate buffer pair / 5mM 5mM hydrochloric acid / Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 97 was prepared with reference to the formulation of Example 3 in patent CN103860463A.
  • Example 98 and Example 99 respectively measure 1000mL of water, add 1.051g of citric acid, 0.228g of sodium hydroxide, stir to dissolve, add 4g of sodium chloride, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with a proper amount of hydrochloric acid, and finally add The prescription amount of indacaterol maleate is stirred and dissolved in ampoules.
  • Example 97 Measure 1000 mL of water, add 2 g of disodium hydrogen phosphate, 7.5 g of dipotassium hydrogen phosphate, 0.5 g of sodium chloride, 0.0225 g of sodium formaldehyde sulfoxylate, and 0.05 g of ethylenediaminetetraacetic acid-calcium disodium.
  • Example 97 prepared by the example prescription in the patent CN103860463A
  • the impurities in Example 97 increase significantly during the room temperature storage process, and the amount of impurities has exceeded 1% after being placed for 3 months.
  • the impurity increased slightly after being left for 3 months, and there was no significant difference in impurity growth between the two examples.
  • indacaterol maleate and glycopyrrolate are pulverized and pretreated with a jet mill to make the particle size D 90 ⁇ 5 ⁇ m, and then indacaterol maleate, glycopyrrolate and magnesium stearate are mixed uniformly , And then gradually mixed with lactose according to the same amount of stepwise addition, and the total mixed powder obtained is filled in the capsule.
  • the fine particle fraction (Fine Particle Fraction, FPF) reflects the proportion of the amount of medicine that the inhalation preparation can enter the lungs.
  • FPF Fraction
  • Example 34 Example 68, Example 79, Example 82, Example 87, and Example 100
  • the FPF value of the preparation was determined by using a next generation pharmaceutical impactor (NGI). Using different flow rates to simulate changes in FPF values in different embodiments under different breathing modes.
  • NTI next generation pharmaceutical impactor
  • Example 34 The test results show that the FPF values of the inhaled solutions of Example 34, Example 68, Example 79, Example 82, and Example 87 are not significantly different at different flow rates, and the proportion of fine particles reaching the lungs in the preparation will not vary depending on the person.
  • the breathing capacity of the powder is different; and the FPF value of the powder aerosol of Example 100 at different flow rates is quite different.
  • the FPF value at low flow rates is significantly lower, and the glycopyrrolate is more significantly lower, so the powder aerosol It has certain limitations for patients with weak breathing ability, and the inhalation solution of the present invention overcomes this shortcoming.
  • Preparation method Measure 1000mL of water, add prescription amount of citric acid and sodium citrate, stir until completely dissolved, then add prescription amount of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add to the table
  • the prescription amount of indacaterol maleate and aclidinium bromide shown in the formula stir overnight until the raw material is completely dissolved, then add the prescription amount of budesonide or ciclesonide or beclomethasone dipropionate and mix well. Dispense them into ampoules and test the concentration. The test results are as follows:
  • test results show that indacaterol maleate and aclidinium bromide can be combined with different steroid hormone drugs to prepare a ternary compound inhalation solution.
  • Example 109 Example 110
  • Example 111 Example 112 Indacaterol maleate 0.108g 0.108g 0.08g 0.13g Glycopyrrolate / 0.058g 0.046g 0.07g Sodium acetate / / / / ascorbic acid / / / / Citric acid 0.699g 0.699g 0.699g 0.699g Sodium citrate 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g Sodium chloride 6g 6g 6g 6g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 107 and Example 108 are samples prepared according to the recipe process of Example 1 and Example 2 in patent CN103860463A, respectively.
  • Example 109 Measure the prescription amount of water, add the prescription amount of citric acid and sodium citrate, stir to dissolve, add the prescription amount of sodium chloride, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount Indacaterol maleate, stir to dissolve and filter, and dispense into ampoules.
  • Example 107 to Example 110 were placed in a thermostat at 25 ⁇ 2° C. to investigate the changes of related substances during the placement of the samples.
  • Example 107 and Example 108 prepared with reference to the formulations of Example 1 and Example 2 in the patent CN103860463A, the content of related substances of indacaterol increased significantly during storage at room temperature, and it exceeded that after 3 months of storage. Increased by 0.8% to 1.0%.
  • the samples of Example 109 and Implementation 110 prepared according to the technical scheme of the present invention only slightly increased the content of indacaterol related substances after being placed at room temperature for 3 months, and the stability of indacaterol maleate was significantly better than that in CN103860463A.
  • Example 1 The samples of Example 1 and Example 2; and there was no significant difference in the growth of related substances of indacaterol between the samples of Example 109 and Example 110, indicating that the addition of glycopyrrolate in the composition of the present invention will not Affecting the stability of indacaterol maleate, there is no compatibility problem between indacaterol maleate and glycopyrrolate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

一种吸入溶液药物组合物及其制备方法，所述组合物包含茚达特罗或其盐、pH调节剂和水，以及任选的渗透压调节剂、缓冲离子对，通过将各组分溶解于水中制得。该药物组合物适合于借助于雾化器而将活性物质形成气雾以在哮喘及COPD症状中以吸入方式对患者施用。

Description

一种吸入溶液药物组合物及其制备方法 技术领域
本发明涉及一种吸入溶液药物组合物，具体涉及一种含茚达特罗的吸入溶液药物组合物，属于药物制剂领域。
背景技术
全球大约有4200万哮喘病患者和2800万慢性阻塞性肺病(COPD)患者。近十年来，随着全球范围内的空气污染和环境恶化，哮喘症的发病率和死亡率呈上升趋势，每年有超过18万人死于哮喘。另有分析显示，到2020年，COPD将从现在的全球死因的第六位攀升至第三位。临床上COPD的治疗药物主要包括长效β2-受体激动剂(LABA)、长效抗胆碱能药物(LAMA)和类固醇激素这几类，这些药物采用局部肺部吸入给药，疗效佳且安全性好。
茚达特罗是一种新型的长效β2-受体激动剂(LABA)，由瑞士诺华制药公司生产，2009年以来已在全球70多个国家和地区上市，2012年6月经中国国家药监局批准在华上市，是中国首个获批用于治疗COPD的LABA类单一制剂。现有上市的茚达特罗单方吸入制剂只有昂润
Figure PCTCN2020120348-appb-000001
(马来酸茚达特罗吸入粉雾剂)这一种粉雾剂剂型。干粉吸入的给药方式需要病人学习吸药方法且需要病人有较好的肺功能以吸入药物，对于一些严重COPD病人而言，其肺功能差，可能无法达到吸入粉雾剂所需的吸入气流，药物因此无法有效递送到肺部或吸入的剂量不足，使药物疗效下降。而采用雾化吸入给药，病人无需要特殊训练，尤其对于严重COPD患者，采用正常呼吸方式即可吸入足够剂量的药物，因此有必要开发茚达特罗的吸入溶液以满足临床上此类病人的需求。
CN103860463A公开了一种含马来酸茚达特罗的溶液及其吸入喷雾剂，其公布的处方中马来酸茚达特罗的浓度非常低，仅为2.0mcg/mL～15mcg/mL。吸入溶液在临床使用时一般要求雾化时间控制在10分钟以内，如果雾化溶液的体积过大，雾化时间会显著增长而无法满足临床的需求，一般吸入溶液的体积需控制在3mL以内。假设马来酸茚达特罗吸入溶液(药物浓度15mcg/mL)中药物的总量与已上市的昂润
Figure PCTCN2020120348-appb-000002
(马来酸茚达特罗吸入粉雾剂)的规格(以茚达特罗计150mcg)保持一致，则该雾化溶液的体积需要10mL以上，远远高于常规雾化溶液的体积。很显然，该马来酸茚达特罗吸入溶液中药物浓度过低，导致雾化溶液体积过大且雾化吸入时间过长，并不能满足临床上的需求。本案发明人根据CN103860463A中的实施例，在其基础上试图直接增大马 来酸茚达特罗的加入量来提高其在水溶液中的浓度，但未能实现。受马来酸茚达特罗在水中的溶解特性较差的影响，马来酸茚达特罗在水溶液中较为容易析出；加之马来酸茚达特罗在水溶液中的稳定性也较差，特别是在较高浓度情况下更是如此。因此开发一种具有较高马来酸茚达特罗含量的储存稳定的吸入溶液是本领域亟待解决的问题。迄今为止还未见有关于高浓度的马来酸茚达特罗吸入溶液的研究报道。
杰润
Figure PCTCN2020120348-appb-000003
(茚达特罗格隆溴铵吸入粉雾剂)是一种新型的治疗COPD的吸入制剂，该产品为含有两种支气管扩张剂的复方粉雾剂，其中茚达特罗为长效β2-受体激动剂(LABA)，格隆溴铵为长效抗胆碱能(LAMA)药物。作为全球第一个上市的LABA/LAMA类药物，茚达特罗格隆溴铵在阻断M3受体的同时可激动β2受体，具有强大的协同作用，较单药治疗能够显著提高肺功能，为COPD的治疗带来了更好的治疗手段。但该产品只有吸入粉雾剂这一种剂型，对于一些严重COPD病人而言，由于其肺功能差，可能无法达到吸入粉雾剂所需的吸入气流，药物无法有效递送到肺部或递送剂量下降，使药物疗效下降。而采用雾化吸入给药，病人无需要特殊训练，尤其对于严重COPD患者，采用正常呼吸方式即可吸入足够剂量的药物。因此，开发茚达特罗格隆溴铵的复方吸入溶液，可以很好地满足临床上这类病人的需求。但是，到目前为止也还没有关于茚达特罗格隆溴铵复方吸入溶液的研究报道。
发明内容
为了解决现有技术的不足，本发明一个目的在于提供一种含茚达特罗或其盐的吸入溶液药物组合物，该组合物中的药物浓度足够高，可以满足临床上对吸入溶液的体积要求，使用时借助手动泵、超声喷雾、空气压缩机等压力将内容物呈雾状释出，是用于肺部吸入的制剂。此外，该组合物中氯化钠的浓度高，可以有助于减小呼吸道刺激，保持雾滴粒径稳定。
本发明的另一目的是提供一种稳定的茚达特罗格隆溴铵复方吸入溶液处方及其制备方法，该制剂中药物浓度高且制剂具有良好的化学稳定性，可以很好地满足临床的需求。
本发明的技术方案如下：
一种吸入溶液药物组合物，其包含活性成分茚达特罗或其药学上可接受的盐、pH调节剂和水，其中活性成分茚达特罗或其药学上可接受的盐的浓度以茚达特罗计为23.2mcg/mL～231.5mcg/mL，其pH为2.0～5.5。
在一实施方案中，所述活性成分茚达特罗药学上可接受的盐包括马来酸茚达特罗或醋酸茚达特罗。
在一实施方案中，本发明的吸入溶液药物组合物，其每1mL含马来酸茚达特罗30mcg～300mcg，其pH为3.0～4.0。
在一实施方案中，所述pH调节剂选自盐酸、硫酸、醋酸、磷酸、马来酸、柠檬酸、乳酸、氨基酸、氢氧化钠、碳酸钠、碳酸氢钠、磷酸钠、磷酸氢二钠中的一种或多种的组合，所述药物组合物的pH值为2.5～5.0。
在一实施方案中，所述药物组合物还包含其它辅料，所述其它辅料选自增溶剂、渗透压调节剂、缓冲离子对中的至少一种。
在一实施方案中，所述增溶剂选自聚山梨酯、聚乙二醇蓖麻油、聚氧乙烯蓖麻油、卵磷脂中的至少一种。
在一实施方案中，所述渗透压调节剂选自氯化钠或甘露醇中的至少一种。
在一实施方案中，所述缓冲离子对选自柠檬酸-柠檬酸钠缓冲对、磷酸氢二钠-磷酸二氢钠缓冲对、碳酸氢钠-碳酸钠缓冲对、醋酸-醋酸钠缓冲对、酒石酸-酒石酸钠缓冲对，所述缓冲离子对的浓度为1mM～50mM。此处所述的缓冲离子对的浓度，是以缓冲离子对中起到缓冲作用的酸根的总摩尔浓度计算，比如配制浓度为6mM的柠檬酸-柠檬酸钠缓冲对，此处所述的6mM是指柠檬酸根的摩尔浓度为6mM，可以通过向1000mL水中加入4mmol的柠檬酸和2mmol的柠檬酸钠制得。
在一实施方案中，所述缓冲离子对的浓度为3mM～30mM。
在一实施方案中，所述柠檬酸-柠檬酸钠缓冲对可以用柠檬酸和氢氧化钠配制得到，使用的柠檬酸选自无水柠檬酸、柠檬酸一水合物中的一种或多种的组合。
在一实施方案中，所述柠檬酸-柠檬酸钠缓冲对可以用柠檬酸和柠檬酸钠配制得到，使用的柠檬酸选自无水柠檬酸、柠檬酸一水合物中的一种或多种的组合，使用的柠檬酸钠选自无水柠檬酸钠、柠檬酸钠二水合物、柠檬酸钠五水合物中的一种或多种的组合。
在一实施方案中，本发明所述的pH4.0的柠檬酸-柠檬酸钠缓冲对可以由柠檬酸和柠檬酸钠在水溶液中配制而得，其中柠檬酸和柠檬酸钠加入量的摩尔配比为2:1。比如配制浓度为5mM的pH4.0的柠檬酸-柠檬酸钠缓冲对，可以通过向1000mL水中加入3.34mmol的柠檬酸和1.67mmol的柠檬酸钠制得。
在一实施方案中，所述药物组合物还包含短链醇，所述短链醇选自乙醇、丙二醇、丙三醇中的一种或多种的组合。
在一实施方案中，所述茚达特罗或其药学上可接受的盐的重量百分含量以茚达特罗计为23.2mcg/mL～77.2mcg/mL时，所述渗透压调节剂的含量为0.1％～0.9％。
在一实施方案中，所述茚达特罗或其药学上可接受的盐的重量百分含量以茚达特 罗计为77.3mcg/mL～231.5mcg/mL时，所述渗透压调节剂的含量为0.1％～0.7％。
在一实施方案中，本发明的吸入溶液药物组合物中，所述马来酸茚达特罗的含量为30mcg/mL～100mcg/mL，所述渗透压调节剂的含量为0.3g/mL～0.9g/mL。
在一实施方案中，本发明的吸入溶液药物组合物中，所述马来酸茚达特罗的含量为100mcg/mL～300mcg/mL，所述渗透压调节剂的含量为0.3g/mL～0.7g/mL。
在一实施方案中，当短链醇为乙醇时，其重量百分含量为0.02％～0.08％。
在一实施方案中，当短链醇为丙二醇时，丙二醇与水的重量比为1:4～200。
在一实施方案中，当短链醇为丙三醇时，丙三醇与水的重量比为1:20～200。
在一实施方案中，所述药物组合物还进一步包含活性成分格隆溴铵、噻托溴铵、异丙托溴铵、乌美溴铵、阿地溴铵、布地奈德、环索奈德、丙酸倍氯米松、糠酸莫米松、丙酸氟替卡松、糠酸氟替卡松中的至少一种，这些活性成分在所述药物组合物中的浓度各自独立地为20mcg/mL～500mcg/mL。
在一实施方案中，所述药物组合物还进一步包含格隆溴铵，每1000mL所述药物组合物含所述格隆溴铵0.05～0.5g。
在一实施方案中，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，氯化钠3g～7g，一水柠檬酸0.6g～2.8g，二水柠檬酸钠0.4g～2.0g，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
在一实施方案中，所述药物组合物每1000mL包含：马来酸茚达特罗0.108g，格隆溴铵0.058g，一水柠檬酸0.699g，二水柠檬酸钠0.492g，氯化钠6g，pH调节剂适量调pH至4.0，加水至1000mL。
在一实施方案中，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，一水柠檬酸0.6g～2.8g，二水柠檬酸钠0.4g～2.0g，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
在一实施方案中，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，一水柠檬酸0.6g～2.8g，二水柠檬酸钠0.4g～2.0g，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
在一实施方案中，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，氯化钠3g～7g，由一水柠檬酸0.5g～4g和氢氧化钠0.1g～0.8g反应得到的柠檬酸-柠檬酸钠缓冲对，pH调节剂适量调 pH至2.5～5.0，水加至1000mL。
在一实施方案中，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，由一水柠檬酸0.5g～4g和氢氧化钠0.1g～0.8g反应得到的柠檬酸-柠檬酸钠缓冲对，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
在一实施方案中，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，由一水柠檬酸0.5g～4g和氢氧化钠0.1g～0.8g反应得到的柠檬酸-柠檬酸钠缓冲对，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
进一步地，上述pH调节剂选自盐酸、硫酸、醋酸、磷酸、马来酸、柠檬酸、乳酸、氨基酸、氢氧化钠、碳酸钠、碳酸氢钠、磷酸钠或磷酸氢二钠中的一种或多种。
在一实施方案中，本发明所述柠檬酸-柠檬酸钠缓冲对由柠檬酸和柠檬酸钠在水溶液中配制而得。此缓冲对同样也可以用其他方式制得，比如使用柠檬酸和氢氧化钠在水溶液中配制而得，或者使用柠檬酸钠和盐酸在水溶液中配制而得。
本发明中所述mcg为质量单位微克，即μg。
本发明中所使用的柠檬酸均为柠檬酸一水合物。使用无水柠檬酸或者其他类型的柠檬酸水合物也可以达到和使用柠檬酸一水合物同样的技术效果，也属于本发明的范畴。
本发明中所使用的柠檬酸钠均为柠檬酸钠二水合物。使用无水柠檬酸钠或者其他类型的柠檬酸钠水合物比如五水柠檬酸钠也可以达到和使用柠檬酸钠二水合物同样的技术效果，也属于本发明的范畴。
本发明还提供了茚达特罗吸入溶液药物组合物的制备方法，其包括如下步骤：
(a)往水中加入处方量的辅料，辅料选自增溶剂、渗透压调节剂、缓冲离子对、短链醇中的至少一种，搅拌使辅料分散溶解且用pH调节剂将溶液pH调整到目标值2.0～5.5；
(b)向(a)中制备的辅料溶液中加入处方量的茚达特罗或其药学上可接受的盐，搅拌溶解；可选地，再加入格隆溴铵、噻托溴铵、异丙托溴铵、乌美溴铵、阿地溴铵中的至少一种，搅拌溶解。
可选地，将上述(b)得到的药物溶液过滤除菌，例如用小于或等于0.22μm的滤膜进行过滤除菌，得无菌的药物溶液。
可选地，向无菌的药物溶液中再加入无菌的布地奈德、环索奈德、丙酸倍氯米松、糠酸莫米松、丙酸氟替卡松、糠酸氟替卡松中的至少一种，搅拌分散均匀。
可选地，将得到的无菌药物溶液分装，例如灌装于西林瓶、玻璃安瓿或塑料安瓿 中，得到茚达特罗吸入溶液药物组合物。
在一实施方案中，本发明提供了一种茚达特罗吸入溶液药物组合物的制备方法，所述制备方法包括如下步骤：
(a)往水中加入处方量的辅料，辅料选自增溶剂、渗透压调节剂、缓冲离子对、短链醇中的至少一种；搅拌均匀使辅料分散溶解后，用pH调节剂将溶液pH调整到目标值2.0～5.5；
(b)向(a)中制备的辅料溶液中加入处方量的茚达特罗或其药学上可接受的盐，搅拌溶解；
(c)将(b)得到的药物溶液用小于或等于0.22μm的滤膜进行过滤除菌，得无菌的药物溶液；
(d)将(c)得到的无菌药物溶液灌装于西林瓶、玻璃安瓿或塑料安瓿中，得到茚达特罗吸入溶液药物组合物。
本发明还提供了另一种所述的茚达特罗吸入溶液药物组合物的制备方法，所述制备方法包括如下步骤：
(a)往水中加入处方量的辅料，辅料选自增溶剂、渗透压调节剂、缓冲离子对、短链醇中的至少一种；搅拌均匀使辅料分散溶解后，用pH调节剂将溶液pH调整到目标值2.0～5.5；
(b)向(a)中制备的辅料溶液中加入处方量的茚达特罗或其药学上可接受的盐，并加入格隆溴铵、噻托溴铵、异丙托溴铵、乌美溴铵、阿地溴铵中的至少一种，搅拌溶解；
(c)将(b)得到的药物溶液用小于或等于0.22μm的滤膜进行过滤除菌，得无菌的药物溶液；
(d)将(c)得到的无菌药物溶液灌装于西林瓶、玻璃安瓿或塑料安瓿中，得到茚达特罗吸入溶液药物组合物。
在一实施方案中，本发明还提供了另一种所述的茚达特罗吸入溶液药物组合物的制备方法，所述制备方法包括如下步骤：
(a)往水中加入处方量的辅料，辅料选自增溶剂、渗透压调节剂、缓冲离子对、短链醇中的至少一种；搅拌均匀使辅料分散溶解后，用pH调节剂将溶液pH调整到目标值2.0～5.5；
(b)向(a)中制备的辅料溶液中加入处方量的茚达特罗或其药学上可接受的盐，搅拌溶解；
(c)将(b)得到的药物溶液用小于或等于0.22μm的滤膜进行过滤除菌，得无菌的药物溶液；
(d)向(c)得到的无菌药物溶液中加入无菌的布地奈德、环索奈德、丙酸倍氯米松、糠酸莫米松、丙酸氟替卡松、糠酸氟替卡松中的至少一种，搅拌分散均匀。
(e)将(d)得到的无菌药物混悬液灌装于西林瓶、玻璃安瓿或塑料安瓿中，得到茚达特罗吸入溶液药物组合物。
在一实施方案中，本发明还提供了另一种所述的茚达特罗吸入溶液药物组合物的制备方法，所述制备方法包括如下步骤：
(a)往水中加入处方量的辅料，辅料选自增溶剂、渗透压调节剂、缓冲离子对、短链醇中的至少一种；搅拌均匀使辅料分散溶解后，用pH调节剂将溶液pH调整到目标值2.0～5.5；
(b)向(a)中制备的辅料溶液中加入处方量的茚达特罗或其药学上可接受的盐，并加入格隆溴铵、噻托溴铵、异丙托溴铵、乌美溴铵、阿地溴铵中的至少一种，搅拌溶解；
(c)将(b)得到的药物溶液用小于或等于0.22μm的滤膜进行过滤除菌，得无菌的药物溶液；
(d)向(c)得到的无菌药物溶液中加入无菌的布地奈德、环索奈德、丙酸倍氯米松、糠酸莫米松、丙酸氟替卡松、糠酸氟替卡松中的至少一种，搅拌分散均匀。
(e)将(d)得到的无菌药物混悬液灌装于西林瓶、玻璃安瓿或塑料安瓿中，得到茚达特罗吸入溶液药物组合物。
本发明提供的茚达特罗吸入溶液药物组合物，克服了现有茚达特罗吸入溶液浓度低而无法临床应用的缺陷，且处方中可加入较高浓度的氯化钠且保持茚达特罗的高浓度，大大提高了茚达特罗在吸入溶液制剂中的浓度，顺利实现了茚达特罗吸入溶液制剂大规格制剂的制备，这种高浓度的茚达特罗吸入溶液更好地满足了临床需求。本发明所提供的茚达特罗格隆溴铵复方吸入溶液组合物为首次报道，该制剂中药物浓度高且制剂具有良好的化学稳定性，可以很好地满足临床的需求；另一方面，本发明吸入溶液在不同气流速下的FPF值差异较小(干粉吸入制剂的则较大)，不同吸气能力的患者均可适用(干粉吸入制剂不适于吸气能力弱的患者)，提高了病人用药的顺应性。
具体实施方式
下面结合试验例及实施例对本发明作进一步说明，可使本领域专业技术人员更全 面地理解本发明，但不以任何方式限制本发明。
试验例1～8：研究马来酸茚达特罗在不同pH溶液中的溶解度
Figure PCTCN2020120348-appb-000004
制备方法：量取1000mL水，加入适量盐酸调节pH至处方中载明的pH值，误差范围不超过±0.05，然后加入0.5g马来酸茚达特罗原料药，25℃搅拌24小时，过滤后检测样品浓度。
检测结果：
Figure PCTCN2020120348-appb-000005
检测结果表明在pH 2.0～5.5的溶液中，每1毫升可以溶解大约100～300mcg的马来酸茚达特罗药物，并且在低pH溶液中，马来酸茚达特罗的溶解度更高。
试验例9～14：研究在不同pH条件下茚达特罗溶液的稳定性。
  试验例9 试验例10 试验例11 试验例12 试验例13 试验例14
马来酸茚达特罗 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g
pH 3.0 3.5 4.0 4.5 5.0 5.5
加水至 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
制备方法：分别量取1000mL水，用适量盐酸调节溶液pH至处方中载明的pH值，误差范围不超过±0.05，然后分别加入0.15g马来酸茚达特罗原料药，搅拌过夜，过滤灌封于安瓿瓶中，分别放置于4℃、25℃条件下，分别于1、2、3月检查样品有关物质。
检测结果：
Figure PCTCN2020120348-appb-000006
检测结果表明，在4℃条件下，试验例9-14的杂质量与0天对比没有明显变化，同时随温度的升高，试验例9-14的杂质量均有所增加。发明人还发现pH5.0～5.5的溶 液中，25℃条件下3个月杂质量超过了1％。因此pH3.0～4.5的溶液中，马来酸茚达特罗在25℃条件下更加稳定。
因为试验例9-14的结果显示，马来酸茚达特罗在pH3.0～5.5的溶液中，低温保存更稳定，因此需要考察在低温保存时，马来酸茚达特罗是否还能有较高的溶解度。
试验例15～18：考察在低温保存时马来酸茚达特罗在不同pH溶液中的溶解度
  试验例15 试验例16 试验例17 试验例18
马来酸茚达特罗 0.3g 0.3g 0.3g 0.3g
盐酸 适量 / / /
柠檬酸-柠檬酸钠缓冲对 / 5mM 5mM 5mM
pH 3.0 4.0 4.5 5.0
加水至 1000mL 1000mL 1000mL 1000mL
量取1000mL水，试验例15加入适量盐酸，调节pH至3.00±0.05；试验例16～18加入柠檬酸0.699g、柠檬酸钠0.492g，搅拌溶解后调节pH至处方载明pH，误差范围不超过±0.05，然后加入0.3g马来酸茚达特罗药物，搅拌过夜，过滤分装于安瓿瓶中，于2-8℃冰箱中保存，分别测试0时间和72小时时样品浓度和pH值。浓度测试前需要先将安瓿瓶中的样品进行过滤处理以除去未溶解的药物颗粒。检测结果为：
Figure PCTCN2020120348-appb-000007
从上述检测结果可以看出，低温条件下，溶液pH控制在3.0～4.0时，马来酸茚达特罗的溶解度较高。而当pH＞4.0时，溶解度开始显著下降，并且随pH值升高而降低；低温保存过程中，药物浓度没有明显变化。
在吸入溶液中，需要加入渗透压调节剂，常用氯化钠调节溶液渗透压。但是本发明在研究中发现氯化钠会影响马来酸茚达特罗的溶解度，因此需考察不同浓度的氯化钠对马来酸茚达特罗溶解度的影响。
试验例19～27：考察氯化钠浓度对马来酸茚达特罗溶解度的影响
Figure PCTCN2020120348-appb-000008
制备方法：量取1000mL水，试验例19～21加入柠檬酸0.699g、柠檬酸钠0.492g；试验例22～24加入柠檬酸1.398g、柠檬酸钠0.984g；试验例25～27加入柠檬酸2.796g、柠檬酸钠1.968g，搅拌至完全溶解，再加入对应的氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至4.00±0.05，然后加入0.3g马来酸茚达特罗原料药，搅拌过夜，过滤后分装于安瓿瓶中。测试药液浓度和pH值。同时放置于2-8℃冰箱中分别放置3天、7天，测定样品浓度和pH值。浓度测试前需要先将安瓿瓶中的样品进行过滤处理以除去可能的析出药物颗粒。
检测结果为：
Figure PCTCN2020120348-appb-000009
上述检测结果表明，在含有氯化钠的溶液中，马来酸茚达特罗的溶解度降低(能观察到有白色颗粒状析出物)。并且氯化钠的浓度越高，则马来酸茚达特罗的溶解度越低，且在放置过程中更容易析出。同时本发明发现柠檬酸-柠檬酸钠缓冲对可以提高马来酸茚达特罗在含有氯化钠的溶液中溶解度，降低放置过程中药物析出的风险。
为明确柠檬酸-柠檬酸钠缓冲对在溶液中的浓度，需研究不同浓度的柠檬酸-柠檬酸钠缓冲对对马来酸茚达特罗在氯化钠溶液中溶解度的影响。
试验例28～32：考察柠檬酸-柠檬酸钠缓冲对对于马来酸茚达特罗在氯化钠溶液中溶解度的影响
处方：
  试验例28 试验例29 试验例30 试验例31 试验例32
马来酸茚达特罗 0.2g 0.2g 0.2g 0.2g 0.2g
柠檬酸-柠檬酸钠缓冲对 - 5mM 20mM 30mM 50mM
氯化钠 6g 6g 6g 6g 6g
盐酸 适量 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL 1000mL
制备方法：量取1000mL水，其中试验例29～32分别加入柠檬酸0.699g、1.398 g、4.194g、6.990g，柠檬酸钠0.492g、1.968g、2.952g、4.920g，搅拌至完全溶解。试验例28～32再分别再加入6g氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至4.00±0.05，然后加入0.2g马来酸茚达特罗原料药，搅拌过夜，过滤后分装于安瓿瓶中测试样品浓度和pH值。浓度测试前需要先将安瓿瓶中的样品进行过滤处理以除去可能的析出药物颗粒。同时放置于2-8℃冰箱中分别放置7天后进行再次检测。浓度测试前需要先将安瓿瓶中的样品进行过滤处理以除去可能的析出药物颗粒。
检测结果为：
Figure PCTCN2020120348-appb-000010
根据试验例28-32的检测结果表明，柠檬酸-柠檬酸钠缓冲对可以增加马来酸茚达特罗在氯化钠溶液中的溶解度，并且能够降低马来酸茚达特罗在放置过程中析出的风险。
试验例33：考察按照专利CN103860463A中实施例1的处方是否能制备出高浓度且稳定的马来酸茚达特罗溶液。
处方：
马来酸茚达特罗 0.1g
柠檬酸 1.5g
柠檬酸钠 4g
氯化钠 2g
水 1000mL
备注：处方中除了马来酸茚达特罗的浓度提高外，其他辅料的浓度均与专利CN103860463A中实施例1一致。
按照上述处方量称取各个辅料，加入1000mL水中，搅拌至完全溶解，然后加入0.1g的马来酸茚达特罗药物，搅拌溶解后调节pH至5.0±0.05，过滤后灌封于安瓿瓶中，检测样品浓度，同时将样品放置在2～8℃冰箱中保存7天，检测样品浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  0天 7天
以茚达特罗计浓度(mcg/mL) 77.27 60.46
放置7天后，马来酸茚达特罗浓度降低，并且观察到安瓿瓶中有析出物。以上结果表明按照专利CN103860463A中实施例1的处方无法制备出高浓度的马来酸茚达特 罗溶液。
试验例34：考察按照专利CN103860463A中实施例3的处方是否能制备出高浓度且稳定的马来酸茚达特罗溶液
处方：
马来酸茚达特罗 0.02g
磷酸氢二钠 2g
磷酸氢二钾 7.5g
氯化钠 0.5g
甲醛合次硫酸氢钠 22.5mg
乙二胺四乙酸一钙二钠 50mg
水 1000mL
备注：处方中除了马来酸茚达特罗的浓度提高外，其他辅料的浓度均与专利CN103860463A中实施例3一致。
按照上述处方量称取各个辅料，加入1000mL水中，搅拌至完全溶解，然后加入0.02g的马来酸茚达特罗药物，搅拌溶解后调节pH至6.5±0.05，过滤后灌封于安瓿瓶中，检测样品浓度，同时将样品放置在2～8℃冰箱中保存7天，检测样品浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  0天 7天
以茚达特罗计浓度(mcg/mL) 15.42 5.17
放置7天后，马来酸茚达特罗浓度降低，并且观察到安瓿瓶中有析出物。以上结果表明按照专利CN103860463A中实施例3的处方无法制备出高浓度的马来酸茚达特罗溶液。
实施例1～8：
处方：
Figure PCTCN2020120348-appb-000011
制备方法：量取1000mL水并加入0.1g的聚山梨酯-80溶解，用盐酸调节pH至处方载明pH，误差范围不超过±0.05，然后加入对应量的马来酸茚达特罗药物，在室温条件下搅拌溶解，过滤后灌封于安瓿瓶中，检测样品浓度和有关物质。浓度测试前需要先将安瓿瓶中的样品进行过滤处理以除去可能的析出药物颗粒。
检测结果：
  以茚达特罗计浓度(mcg/mL) 有关物质(％)
实施例1 77.41 0.133
实施例2 229.76 0.138
实施例3 76.64 0.129
实施例4 231.07 0.117
实施例5 78.87 0.122
实施例6 230.23 0.123
实施例7 76.95 0.163
实施例8 228.98 0.149
结果表明：在pH2.0～5.0范围内，可以得到浓度100～300mcg/mL的马来酸茚达特罗溶液。
实施例9～11：
处方：
  实施例9 实施例10 实施例11
马来酸茚达特罗 0.2g 0.2g 0.2g
聚乙二醇蓖麻油 / / 1g
卵磷脂 / 1g /
聚氧乙烯蓖麻油 0.4g / /
pH 4.0 4.0 4.0
加水至 1000mL 1000mL 1000mL
制备方法：量取1000mL水，按照上述实施例分别加入对应量的聚乙二醇蓖麻油、卵磷脂、聚氧乙烯蓖麻油，待完全溶解后用盐酸调节pH至4.0±0.05，然后加入马来酸茚达特罗药物0.2g，在室温条件下搅拌溶解，过滤后灌封于安瓿瓶中，检测样品浓度和有关物质。浓度测试前需要先将安瓿瓶中的样品进行过滤处理以除去可能的析出药物颗粒。
检测结果：
  以茚达特罗计的浓度(mcg/mL) 有关物质(％)
实施例9 154.20 0.132
实施例10 159.29 0.121
实施例11 155.59 0.133
结果表明：制备的吸入溶液含量、有关物质均符合要求。
实施例12～13：
  实施例12 实施例13
马来酸茚达特罗 0.05g 0.05g
硫酸 适量 /
赖氨酸 / 适量
pH 4.0 4.0
加水至 1000mL 1000mL
制备方法：量取1000mL水，分别用硫酸或赖氨酸调节pH至4.0±0.05，加入0.05g马来酸茚达特罗药物，在室温条件下搅拌溶解，过滤后灌封于安瓿瓶中，检测样品浓度和有关物质。浓度测试前需要先将安瓿瓶中的样品进行过滤处理以除去可能的析出药物颗粒。
检测结果
  以茚达特罗计的浓度(mcg/mL) 有关物质(％)
实施例12 39.05 0.124
实施例13 38.70 0.127
结果表明：氨基酸或硫酸作为pH调节剂，对马来酸茚达特罗溶液的有关物质不会产生影响，溶液的有关物质符合要求。
实施例14～19：
Figure PCTCN2020120348-appb-000012
制备方法：量取1000mL水，加入柠檬酸0.699g、柠檬酸钠0.492g，搅拌至完全溶解，再加入6g氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至4.00±0.05，然后加入相应的乙醇、丙二醇、丙三醇，搅拌使混合均匀。分别量取1000mL对应溶液，加入0.15g马来酸茚达特罗，搅拌过夜，过滤后分装，测试含量和pH值。2-8℃冰箱中放置3天、7天后测试浓度和pH值。浓度测试前需要先将样品进行过滤处理以除去可能的析出药物颗粒。
检测结果：
Figure PCTCN2020120348-appb-000013
结果表明：含有短链醇的混合溶液系统，能够制备出含量合格的制剂。
实施例20～24：
  实施例20 实施例21 实施例22 实施例23 实施例24
马来酸茚达特罗 0.05g 0.1g 0.1g 0.25g 0.15g
柠檬酸-柠檬酸钠缓冲对 5mM 5mM 5mM 20mM 20mM
氯化钠 3g 6g 9g 3g 6g
盐酸 适量 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL 1000mL
制备方法：量取1000mL水，实施例20～22加入柠檬酸0.699g、柠檬酸钠0.492g；实施例23～24加入柠檬酸2.796g、柠檬酸钠1.968g，搅拌至完全溶解，分别加入对应量的氯化钠，待完全溶解后用盐酸调节pH至4.00±0.05，然后加入对应量的马来酸茚达特罗药物，搅拌过夜，过滤后分装，测试浓度和有关物质。浓度测试前需要先将样品进行过滤处理以除去可能的析出药物颗粒。
检测结果：
  以茚达特罗计浓度(mcg/mL) 有关物质(％)
实施例20 38.94 0.127
实施例21 80.03 0.132
实施例22 78.18 0.137
实施例23 193.33 0.112
实施例24 115.42 0.125
结果表明，茚达特罗溶液浓度为38.6～77.2mcg/mL时，氯化钠的浓度为0.3％～0.9％不会影响含量和pH值，茚达特罗溶液浓度为115.8～192.9mcg/mL时，氯化钠的浓度为0.3％～0.6％不会影响含量和pH值。
实施例25～28：
名称 实施例25 实施例26 实施例27 实施例28
马来酸茚达特罗 0.15g 0.15g 0.15g 0.15g
柠檬酸-柠檬酸钠缓冲对 5mM 5mM 5mM 5mM
氯化钠 3g 4g 5g 6g
盐酸 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL
制备方法：量取1000mL水，加入柠檬酸0.699g、柠檬酸钠0.492g，溶解后加入处方量的氯化钠，搅拌溶解，用适量盐酸调节pH至4.00±0.05，最后加入马来酸茚达特罗药物0.15g，搅拌过夜，过滤后分装，测试浓度和有关物质。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  以茚达特罗计浓度(mcg/mL) 有关物质(％)
实施例25 116.00 0.142
实施例26 119.35 0.133
实施例27 114.84 0.152
实施例28 115.53 0.139
结果表明：茚达特罗溶液浓度为115.8mcg/mL时，不同浓度的氯化钠对其含量和有关物质没有影响。
实施例29～34：
处方：
Figure PCTCN2020120348-appb-000014
制备方法：量取1000mL水，实施例29～31加入柠檬酸0.699g、柠檬酸钠0.492g；实施例32～34加入柠檬酸4.194g、柠檬酸钠2.952g，搅拌至完全溶解，分别加入6g氯化钠，待完全溶解后用盐酸调节pH至4.00±0.05，然后加入对应量的马来酸茚达特罗和格隆溴铵药物，搅拌过夜，过滤后分装，测试浓度、有关物质和pH值。浓度测试前需要过滤除去未溶解的药物。
检测结果：
Figure PCTCN2020120348-appb-000015
结果表明，在含氯化钠和柠檬酸盐的水溶液中，格隆溴铵浓度为50-100mcg/mL时，茚达特罗的浓度可以达到115.8～154.4mcg/mL，并且有关物质没有明显增加。
实施例35～37：
  实施例35 实施例36 实施例37
马来酸茚达特罗 0.15g 0.15g 0.15g
格隆溴铵 0.1g 0.2g 0.2g
聚山梨酯-80 / / 0.05g
柠檬酸-柠檬酸钠缓冲对 20mM 20mM 20mM
氯化钠 3g 3g 3g
盐酸 适量 适量 适量
加水至 1000mL 1000mL 1000mL
制备方法：量取1000mL水，加入柠檬酸2.796g、柠檬酸钠1.968g，搅拌至完全溶解，再加入氯化钠和聚山梨酯-80，搅拌至完全溶解；加入适量盐酸调节pH至 4.00±0.05，然后加入0.15g马来酸茚达特罗和格隆溴铵药物，搅拌溶解，过滤后分装于安瓿瓶中，分别测试两种药物的浓度和有关物质。浓度测试前需要过滤除去未溶解的药物。
检测结果：
Figure PCTCN2020120348-appb-000016
结果表明：两种药物含量均符合要求，并且药物之间没有相容性问题。
同时将实施例24、实施例35～37样品放置于5±2℃的恒温箱中考察样品在放置过程中，有关物质和pH值的变化。
检测结果：
Figure PCTCN2020120348-appb-000017
结果表明：实施例24、实施例35～37样品放置过程中，pH值变化不明显，茚达特罗的有关物质略有增加，但增速缓慢，格隆溴铵杂质基本没有变化，样品稳定性良好。
实施例38～43：
Figure PCTCN2020120348-appb-000018
制备方法：量取1000mL水，实施例41～43加入柠檬酸0.699g、柠檬酸钠0.492g、氯化钠5g，搅拌至完全溶解，用盐酸调节pH至对应pH，误差范围不超过 ±0.05；实施例38～40加入5g氯化钠，搅拌溶解后用盐酸调节pH至对应pH，误差范围不超过±0.05，最后各个实施例分别加入处方量的药物，搅拌溶解，过滤后分装于安瓿瓶中，分别测试浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  以茚达特罗计浓度(mcg/mL) 格隆溴铵浓度(mcg/mL)
实施例38 116.23 100.32
实施例39 115.53 100.74
实施例40 115.19 202.42
实施例41 117.15 99.81
实施例42 116.11 204.20
实施例43 115.53 100.84
试验结果表明：在含有0.5％的氯化钠，pH为2～5的溶液中，能制备出浓度合适的吸入溶液。
实施例44～49：
Figure PCTCN2020120348-appb-000019
制备方法：量取1000mL水，加入柠檬酸0.699g、柠檬酸钠0.492g，搅拌至完全溶解，再分别加入处方量氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至4.00±0.05，然后加入0.15g醋酸茚达特罗或茚达特罗和处方量格隆溴铵原料药，搅拌至完全溶解，过滤后分别测试浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
Figure PCTCN2020120348-appb-000020
试验结果表明：醋酸茚达特罗或茚达特罗均可以与格隆溴铵制备为复方吸入溶液。
实施例50～53：
  实施例50 实施例51 实施例52 实施例53
茚达特罗 0.15g 0.15g 0.15g 0.15g
格隆溴铵 0.1g / / /
噻托溴铵 / 0.1g / /
异丙托溴铵 / / 0.1g /
乌美溴铵 / / / 0.1g
柠檬酸-柠檬酸钠缓冲对 5mM 5mM 5mM 5mM
氯化钠 3g 3g 3g 3g
盐酸 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL
制备方法：量取1000mL的水，加入柠檬酸0.699g、柠檬酸钠0.492g，搅拌至完全溶解，再加入3g氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至4.00±0.05，然后加入如上表中所示处方量的药物，搅拌至完全溶解，过滤后分装于安瓿瓶中，分别测试浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
Figure PCTCN2020120348-appb-000021
结果表明，茚达特罗和不同的长效抗胆碱能(LAMA)药物均可以制成复方吸入溶液，并且含量符合要求。
实施例54～59：
Figure PCTCN2020120348-appb-000022
制备方法：量取1000mL水，实施例54～57分别加入柠檬酸0.699g、柠檬酸钠0.492g，搅拌至完全溶解，再分别加入处方量氯化钠，搅拌至完全溶解，加入适量盐酸调节pH至4.00±0.05；实施例58～59加入处方量的氯化钠，搅拌溶解后加入适量盐酸调节pH至3.00±0.05；所有实施例按照处方分别加入马来酸茚达特罗和格隆溴铵， 搅拌过夜待药物溶解后，加入糠酸莫米松或丙酸氟替卡松，搅拌均匀后，分装于安瓿瓶中，分别测试浓度。检测结果如下：
Figure PCTCN2020120348-appb-000023
试验结果表明：在含有0.3％的氯化钠，pH为3～4的溶液中，茚达特罗与不同类型的长效抗胆碱能(LAMA)药物和类固醇激素组成的三元复方吸入溶液，含量符合要求。
实施例60～65：
Figure PCTCN2020120348-appb-000024
制备方法：量取水1000mL，加入处方量的柠檬酸和柠檬酸钠，搅拌至完全溶解，再加入处方量的氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至4.00±0.05，然后加入表中所示处方量的醋酸茚达特罗和格隆溴铵，搅拌过夜至原料药完全溶解，再加入处方量的糠酸莫米松或丙酸氟替卡松或糠酸氟替卡松，搅拌均匀，分装于安瓿瓶中，分别测试浓度。检测结果如下：
Figure PCTCN2020120348-appb-000025
试验结果表明：醋酸茚达特罗、格隆溴铵可以和不同的类固醇激素制备为三元复方吸入溶液。
实施例66～71：
Figure PCTCN2020120348-appb-000026
制备方法：量取1000mL的水，加入处方量的缓冲盐，搅拌至完全溶解，再加入3g氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至表中设定的pH值，然后加入处方量的药物，搅拌至完全溶解，过滤后分装于安瓿瓶中，分别测试浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  以茚达特罗计浓度(mcg/mL) 格隆溴铵浓度(mcg/mL)
实施例66 115.53 100.42
实施例67 114.38 102.73
实施例68 116.11 202.22
实施例69 77.72 299.10
实施例70 45.80 399.69
实施例71 45.94 51.17
实施例72～76：
  实施例72 实施例73 实施例74 实施例75 实施例76
马来酸茚达特罗 0.15g 0.15g 0.15g 0.15g 0.15g
格隆溴铵 0.1g 0.1g 0.1g 0.1g 0.1g
柠檬酸-柠檬酸钠缓冲对 -- 5mM 20mM 5mM 5mM
甘露醇 50g 50g 50g 25g 5g
盐酸 适量 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL 1000mL
制备方法：量取1000mL的水，实施例73、实施例75～76加入柠檬酸0.699g、柠檬酸钠0.492g，实施例74加入柠檬酸2.796g、柠檬酸钠1.968g，搅拌溶解后，各实施例按照处方加入甘露醇，搅拌溶解，用适量盐酸调节pH至4.00±0.05，最后加入处方量的马来酸茚达特罗和格隆溴铵，搅拌溶解，过滤后分装于安瓿瓶中，分别测试浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  以茚达特罗计浓度(mcg/mL) 格隆溴铵浓度(mcg/mL)
实施例72 116.11 100.20
实施例73 117.73 100.52
实施例74 115.42 103.17
实施例75 114.84 99.42
实施例76 118.31 100.71
检测结果表明：甘露醇作为渗透压调节剂，可以制备出含量符合要求的复方吸入溶液。
实施例77～81：
  实施例77 实施例78 实施例79 实施例80 实施例81
马来酸茚达特罗 0.15g 0.15g 0.15g 0.15g 0.15g
格隆溴铵 0.1g 0.1g 0.1g 0.1g 0.1g
柠檬酸-柠檬酸钠缓冲对 5mM 5mM 5mM 10mM 20mM
氯化钠 3g 4g 5g 5g 5g
盐酸 适量 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL 1000mL
制备方法：量取1000mL的水，实施例77～79加入柠檬酸0.699g、柠檬酸钠0.492g；实施例80加入柠檬酸1.398g、柠檬酸钠0.984g；实施例81加入柠檬酸2.796g、柠檬酸钠1.968g，搅拌溶解后各实施例按照处方加入氯化钠，搅拌溶解，用适量盐酸调节pH至3.00±0.05，最后加入处方量的马来酸茚达特罗和格隆溴铵，搅拌溶解，过滤后分装于安瓿瓶中，分别测试浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  以茚达特罗计浓度(mcg/mL) 格隆溴铵浓度(mcg/mL)
实施例77 116.23 100.23
实施例78 117.15 99.83
实施例79 115.19 102.90
实施例80 115.53 101.45
实施例81 116.11 101.27
检测结果表明：pH3.0的溶液中，含有不同浓度的柠檬酸缓冲盐，可以制备出含量符合要求的二元复方吸入溶液。
实施例82～86：
名称 实施例82 实施例83 实施例84 实施例85 实施例86
马来酸茚达特罗 0.25g 0.05g 0.15g 0.15g 0.15g
格隆溴铵 0.1g 0.3g 0.1g 0.1g 0.1g
柠檬酸-柠檬酸钠缓冲对 5mM 5mM 5mM 10mM 40mM
氯化钠 3g 4g 5g 5g 5g
盐酸 适量 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL 1000mL
制备方法：量取1000mL的水，实施例82～84加入柠檬酸1.051g、氢氧化钠0.228g；实施例85加入柠檬酸2.102g、氢氧化钠0.456g；实施例86加入柠檬酸8.408g、氢氧化钠1.824g，搅拌溶解后各实施例按照处方加入氯化钠，搅拌溶解，用适量盐酸调节pH至3.00±0.05，最后加入处方量的马来酸茚达特罗和格隆溴铵，搅拌溶解，过滤后分装于安瓿瓶中，分别测试浓度。浓度测试前需要过滤除去未溶解的药物。
检测结果：
  以茚达特罗计浓度(mcg/mL) 格隆溴铵浓度(mcg/mL)
实施例82 190.13 101.23
实施例83 38.90 299.72
实施例84 116.00 100.23
实施例85 115.49 99.74
实施例86 114.43 100.29
检测结果表明：pH3.0的溶液中，采用柠檬酸和氢氧化钠配制的柠檬酸缓冲对溶液，可以制备出含量符合要求的二元复方吸入溶液。
实施例87～91：
名称 实施例87 实施例88 实施例89 实施例90 实施例91
马来酸茚达特罗 0.12g 0.12g 0.12g 0.12g 0.12g
格隆溴铵 0.06g 0.06g 0.06g 0.06g 0.06g
糠酸莫米松 / / / 0.15g 0.15g
柠檬酸-柠檬酸钠缓冲对 5mM 5mM 5mM 5mM 50mM
氯化钠 4g 5g 6g 4g 5g
盐酸 适量 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL 1000mL
量取1000mL的水，实施例87～90加入柠檬酸1.051g、氢氧化钠0.228g；实施例91加入柠檬酸10.51g，氢氧化钠2.28g。各实施例中柠檬酸和氢氧化钠搅拌溶解后，各实施例按照处方加入氯化钠，搅拌溶解，用适量盐酸调节pH至4.00±0.05，最后加入处方量的马来酸茚达特罗和格隆溴铵，搅拌溶解。实施例87～89过滤后分装于安瓿瓶中，分别测试浓度。实施例90～91过滤后加入处方量的糠酸莫米松，高速剪切分散糠酸莫米松后分装于安瓿瓶中，分别测试浓度。
检测结果：
Figure PCTCN2020120348-appb-000027
检测结果表明：pH4.0的溶液中，采用柠檬酸和氢氧化钠配制的柠檬酸缓冲对溶 液，可以制备出含量符合要求的二元复方吸入溶液和三元复方吸入制剂。
实施例92～96：
名称 实施例92 实施例93 实施例94 实施例95 实施例96
马来酸茚达特罗 0.12g 0.12g 0.12g 0.12g 0.12g
糠酸莫米松 0.5g 0.3g 0.4g 0.15g 0.05g
柠檬酸-柠檬酸钠缓冲对 5mM 5mM 5mM 5mM 50mM
氯化钠 4g 5g 6g 4g 5g
盐酸 适量 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL 1000mL
量取1000mL的水，实施例92～95加入柠檬酸1.051g、氢氧化钠0.228g；实施例96加入柠檬酸10.51g，氢氧化钠2.28g。各实施例中柠檬酸和氢氧化钠搅拌溶解后，各实施例按照处方加入氯化钠，搅拌溶解，用适量盐酸调节pH至4.00±0.05，最后加入处方量的马来酸茚达特罗，搅拌溶解，过滤后加入处方量的糠酸莫米松，高速剪切分散糠酸莫米松后分装于安瓿瓶中，分别测试浓度。
检测结果：
  以茚达特罗计浓度(mcg/mL) 糠酸莫米松浓度(mcg/mL)
实施例92 91.72 507.63
实施例93 90.56 294.31
实施例94 91.16 405.66
实施例95 93.25 147.58
实施例96 94.67 53.12
检测结果表明：pH4.0的溶液中，采用柠檬酸和氢氧化钠配制的柠檬酸缓冲对溶液，可以制备出含量符合要求的茚达特罗糠酸莫米松二元复方吸入溶液。
实施例97～99：
名称 实施例97 实施例98 实施例99
马来酸茚达特罗 0.005g 0.005 0.12
磷酸氢二钠 2g / /
磷酸氢二钾 7.5g / /
氯化钠 0.5g 4g 4g
甲醛合次硫酸氢钠 0.0225g / /
乙二胺四乙酸-钙二钠 0.05g / /
柠檬酸-柠檬酸钠缓冲对 / 5mM 5mM
盐酸 / 适量 适量
加水至 1000mL 1000mL 1000mL
注：实施例97参照专利CN103860463A中实施例3的处方制备。
实施例98、实施例99分别量取1000mL的水，加入柠檬酸1.051g、氢氧化钠0.228g，搅拌溶解后加入4g氯化钠，搅拌溶解，用适量盐酸调节pH至4.00±0.05，最后加入处方量的马来酸茚达特罗，搅拌溶解分装于安瓿瓶中。实施例97量取1000mL 的水，加磷酸氢二钠2g、磷酸氢二钾7.5g、氯化钠0.5g、甲醛合次硫酸氢钠0.0225g、乙二胺四乙酸-钙二钠0.05g，搅拌溶解后得到pH为6.5的缓冲溶液，然后加入0.005g的马来酸茚达特罗，搅拌使溶解后分装于安瓿瓶中。将上述3个实施例样品置于25±2℃的恒温箱中考察样品在放置过程中，有关物质的变化。
检测结果：
Figure PCTCN2020120348-appb-000028
检测结果表明：参照专利CN103860463A中实施例处方制备的实施例97，在室温放置过程中，实施例97杂质增加明显，放置3月后杂质量就已超过了1％。实施例98和实施99，放置3月后杂质略有增加，并且两个实施例之间，杂质增长没有显著差异。
实施例100：
名称 实施例100
马来酸茚达特罗 35.6mg
格隆溴铵 19.5mg
乳糖 24.9g
硬脂酸镁 0.03g
将马来酸茚达特罗和格隆溴铵用气流粉碎机粉碎预处理，使粒径D 90＜5μm，然后将马来酸茚达特罗、格隆溴铵和硬脂酸镁混合均匀，再与乳糖按照等量递加的方式逐步混合，得到的总混粉充填于胶囊中。
在吸入制剂中，微细粒子分数(Fine Particle Fraction，FPF)反映吸入制剂能进入肺部的药物量的比例。FPF值越大，表明吸入制剂中能进入肺部的药物比例越多，吸入制剂的递送效率越高，对肺部疾病的治疗效果越好。
将实施例34、实施例68、实施例79、实施例82、实施例87、实施例100采用新一代药用撞击器(Next generation impactor,NGI)测定制剂的FPF值。采用不同流速模拟不同呼吸方式下，不同实施例FPF值的变化情况。
检测结果：
Figure PCTCN2020120348-appb-000029
Figure PCTCN2020120348-appb-000030
检测结果表明：实施例34、实施例68、实施例79、实施例82、实施例87吸入溶液在不同流速时测试FPF值没有明显差异，制剂中到达肺部的微细粒子的比例不会因人的呼吸能力不同而产生差异；而实施例100粉雾剂在不同流速下的FPF值差异较大，低流速下的FPF值明显较低，且格隆溴铵低得更明显，因此粉雾剂用于呼吸能力弱的患者有一定的局限性，本发明的吸入溶液克服了这一缺陷。
实施例101～106：
Figure PCTCN2020120348-appb-000031
制备方法：量取水1000mL，加入处方量的柠檬酸和柠檬酸钠，搅拌至完全溶解，再加入处方量的氯化钠，搅拌至完全溶解；加入适量盐酸调节pH至4.00±0.05，然后加入表中所示处方量的马来酸茚达特罗和阿地溴铵，搅拌过夜至原料药完全溶解，再加入处方量的布地奈德或环索奈德或丙酸倍氯米松，搅拌均匀，分装于安瓿瓶中，分别测试浓度。检测结果如下：
Figure PCTCN2020120348-appb-000032
试验结果表明：马来酸茚达特罗、阿地溴铵可以和不同的类固醇激素药物组合制备三元复方吸入溶液。
实施例107～112：
名称 实施例109 实施例110 实施例111 实施例112
马来酸茚达特罗 0.108g 0.108g 0.08g 0.13g
格隆溴铵 / 0.058g 0.046g 0.07g
乙酸钠 / / / /
抗坏血酸 / / / /
柠檬酸 0.699g 0.699g 0.699g 0.699g
柠檬酸钠 0.492g 0.492g 0.492g 0.492g
氯化钠 6g 6g 6g 6g
盐酸 适量 适量 适量 适量
加水至 1000mL 1000mL 1000mL 1000mL
实施例107和实施例108分别为按照专利CN103860463A中实施例1和实施例2的处方工艺制备的样品。
实施例109：量取处方量的水，加入处方量的柠檬酸和柠檬酸钠，搅拌溶解后加入处方量的氯化钠，搅拌溶解，用适量盐酸调节pH至4.00±0.05，最后加入处方量的马来酸茚达特罗，搅拌溶解并过滤，分装于安瓿瓶中。
实施例110～实施例112：分别量取处方量的水，加入处方量的柠檬酸和柠檬酸钠，搅拌溶解后加入处方量的氯化钠，搅拌溶解，用适量盐酸调节pH至4.00±0.05，最后加入处方量的马来酸茚达特罗和格隆溴铵，搅拌溶解并过滤，分装于安瓿瓶中。
将实施例107～实施例110样品置于25±2℃的恒温箱中考察样品在放置过程中有关物质的变化。
检测结果：
Figure PCTCN2020120348-appb-000033
检测结果表明：参照专利CN103860463A中实施例1和实施例2处方制备的实施例107和实施例108样品，在室温放置过程中茚达特罗有关物质含量增加明显，放置3个月后就已超过了0.8％～1.0％。而按本发明技术方案制备的实施例109和实施110样品，室温下放置3个月后茚达特罗有关物质含量只是略有增加，其马来酸茚达特罗稳定性显著优于CN103860463A中实施例1、实施例2样品；并且实施例109和实施110这两个实施例样品之间，茚达特罗有关物质增长没有显著差异，说明本发明组合物中格隆溴铵的加入不会影响马来酸茚达特罗的稳定性，马来酸茚达特罗和格隆溴铵之间没有相容性的问题。

Claims (18)

  1. 一种吸入溶液药物组合物，其包含活性成分茚达特罗或其药学上可接受的盐、pH调节剂和水，其中活性成分茚达特罗或其药学上可接受的盐的浓度以茚达特罗计为23.2mcg/mL～231.5mcg/mL，所述药物组合物的pH值为2.0～5.5。
  2. 根据权利要求1所述的药物组合物，其中，活性成分茚达特罗药学上可接受的盐为马来酸茚达特罗或醋酸茚达特罗，所述pH调节剂选自盐酸、硫酸、醋酸、磷酸、马来酸、柠檬酸、乳酸、氨基酸、氢氧化钠、碳酸钠、碳酸氢钠、磷酸钠、磷酸氢二钠中的至少一种，所述药物组合物的pH值为2.5～5.0。
  3. 根据权利要求1或2所述的药物组合物，其还包含其它特定辅料，所述其它特定辅料选自增溶剂、渗透压调节剂、缓冲离子对中的至少一种。
  4. 根据权利要求3所述的药物组合物，其中，所述增溶剂选自聚山梨酯、聚乙二醇蓖麻油、聚氧乙烯蓖麻油、卵磷脂中的至少一种。
  5. 根据权利要求3所述的药物组合物，其中，所述渗透压调节剂选自氯化钠或甘露醇中的至少一种。
  6. 根据权利要求3所述的药物组合物，其中，所述缓冲离子对选自柠檬酸-柠檬酸钠缓冲对、磷酸氢二钠-磷酸二氢钠缓冲对、醋酸-醋酸钠缓冲对、碳酸氢钠-碳酸钠缓冲对、酒石酸-酒石酸钠缓冲对，所述缓冲离子对的浓度为1mM～50mM。
  7. 根据权利要求1～6中任一项所述的药物组合物，其还包含短链醇，所述短链醇选自乙醇、丙二醇、丙三醇中的一种或多种的组合。
  8. 根据权利要求3～7中任一项所述的药物组合物，其中，
    当所述茚达特罗或其药学上可接受的盐的浓度以茚达特罗计为23.2mcg/mL～77.2mcg/mL时，所述渗透压调节剂的重量百分含量为0.1％～0.9％；或者，
    当所述茚达特罗或其药学上可接受的盐的浓度以茚达特罗计为77.3mcg/mL～231.5mcg/mL，所述渗透压调节剂的重量百分含量为0.1％～0.7％。
  9. 根据权利要求7～8中任一项所述的药物组合物，其中，
    当短链醇为乙醇时，其重量百分含量为0.02％～0.08％；或者
    当短链醇为丙二醇时，所述丙二醇与水的重量比为1:4～200；或者
    当短链醇为丙三醇时，所述丙三醇与水的重量比为1:20～200。
  10. 根据权利要求1～9中任一项所述的药物组合物，其还包含活性成分格隆溴铵、噻托溴铵、异丙托溴铵、乌美溴铵、阿地溴铵、布地奈德、环索奈德、丙酸倍氯米 松、糠酸莫米松、丙酸氟替卡松、糠酸氟替卡松中的至少一种，这些活性成分在所述药物组合物中的浓度各自独立地为20mcg/mL～500mcg/mL。
  11. 一种吸入溶液药物组合物，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，氯化钠3g～7g，一水柠檬酸0.6g～2.8g，二水柠檬酸钠0.4g～2.0g，pH调节剂适量调pH至2.5～5.0，水加至1000mL；优选为，所述药物组合物每1000mL包含：马来酸茚达特罗0.108g，格隆溴铵0.058g，一水柠檬酸0.699g，二水柠檬酸钠0.492g，氯化钠6g，pH调节剂适量调pH至4.0，加水至1000mL。
  12. 一种吸入溶液药物组合物，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，一水柠檬酸0.6g～2.8g，二水柠檬酸钠0.4g～2.0g，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
  13. 一种吸入溶液药物组合物，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，一水柠檬酸0.6g～2.8g，二水柠檬酸钠0.4g～2.0g，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
  14. 一种吸入溶液药物组合物，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，氯化钠3g～7g，由一水柠檬酸0.5g～4g和氢氧化钠0.1g～0.8g反应得到的柠檬酸-柠檬酸钠缓冲对，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
  15. 一种吸入溶液药物组合物，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，由一水柠檬酸0.5g～4g和氢氧化钠0.1g～0.8g反应得到的柠檬酸-柠檬酸钠缓冲对，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
  16. 一种吸入溶液药物组合物，所述药物组合物每1000mL包含：茚达特罗或其药学上可接受的盐以茚达特罗计0.04g～0.23g，格隆溴铵0.02g～0.2g，糠酸莫米松0.04g～0.5g，氯化钠3g～7g，由一水柠檬酸0.5g～4g和氢氧化钠0.1g～0.8g反应得到的柠檬酸-柠檬酸钠缓冲对，pH调节剂适量调pH至2.5～5.0，水加至1000mL。
  17. 根据权利要求11～16中任一项所述的吸入溶液药物组合物，其中，所述pH调节剂选自盐酸、硫酸、醋酸、磷酸、马来酸、柠檬酸、乳酸、氨基酸、氢氧化钠、碳 酸钠、碳酸氢钠、磷酸钠、磷酸氢二钠中的至少一种。
  18. 权利要求1～17中任一项所述吸入溶液药物组合物的制备方法，其包括如下步骤：
    (a)往水中加入处方量的辅料，辅料选自增溶剂、渗透压调节剂、缓冲离子对、短链醇中的至少一种，搅拌使辅料分散溶解且用pH调节剂将溶液pH调整到目标值2.0～5.5；
    (b)向(a)中制备的辅料溶液中加入处方量的茚达特罗或其药学上可接受的盐，搅拌溶解；可选地，再加入格隆溴铵、噻托溴铵、异丙托溴铵、乌美溴铵、阿地溴铵中的至少一种，搅拌溶解；
    (c)可选地，将(b)得到的药物溶液用小于或等于0.22μm的滤膜进行过滤除菌，得无菌的药物溶液；可选地，再加入无菌的布地奈德、环索奈德、丙酸倍氯米松、糠酸莫米松、丙酸氟替卡松、糠酸氟替卡松中的至少一种，搅拌分散均匀；
    (d)可选地，将(c)得到的无菌药物溶液灌装于西林瓶、玻璃安瓿或塑料安瓿中，得到茚达特罗吸入溶液药物组合物。
PCT/CN2020/120348 2019-10-11 2020-10-12 一种吸入溶液药物组合物及其制备方法 WO2021068961A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN202210912500.7A CN115998680A (zh) 2019-10-11 2020-10-12 一种吸入溶液药物组合物及其制备方法
CN202080037401.8A CN113853197B (zh) 2019-10-11 2020-10-12 一种吸入溶液药物组合物及其制备方法
CN202210936672.8A CN115337292A (zh) 2019-10-11 2020-10-12 一种吸入溶液药物组合物及其制备方法

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910948205.5 2019-10-11
CN201910948205 2019-10-11
CN202010144174.0 2020-03-06
CN202010144174 2020-03-06

Publications (1)

Publication Number Publication Date
WO2021068961A1 true WO2021068961A1 (zh) 2021-04-15

Family

ID=75436740

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/120348 WO2021068961A1 (zh) 2019-10-11 2020-10-12 一种吸入溶液药物组合物及其制备方法

Country Status (3)

Country Link
CN (3) CN115337292A (zh)
TW (1) TW202114640A (zh)
WO (1) WO2021068961A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023139381A1 (en) * 2022-01-21 2023-07-27 Nanopharm Limited Inhalable formulations
WO2024051683A1 (zh) * 2022-09-05 2024-03-14 立生医药(苏州)有限公司 预防或治疗呼吸系统疾病的吸入用药物组合物

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115381774B (zh) * 2022-08-30 2024-11-22 立生医药(苏州)有限公司 包含长效吸入性类固醇和长效β2受体激动剂组合的药物制剂

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103269694A (zh) * 2010-10-12 2013-08-28 西普拉有限公司 药物组合物
CN103860463A (zh) * 2014-03-11 2014-06-18 熊妲妮 一种含马来酸茚达特罗的溶液及其吸入喷雾剂
WO2019142214A1 (en) * 2018-01-19 2019-07-25 Cipla Limited Pharmaceutical composition comprising tiotropium for inhalation
WO2020019952A1 (zh) * 2018-07-26 2020-01-30 四川海思科制药有限公司 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用
WO2020105012A1 (en) * 2018-11-22 2020-05-28 Glenmark Specialty S.A. Sterile compositions of indacaterol suitable for nebulization
WO2020141472A1 (en) * 2019-01-03 2020-07-09 Glenmark Specialty S.A. Nebulization composition comprising tiotropium and indacaterol

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103269694A (zh) * 2010-10-12 2013-08-28 西普拉有限公司 药物组合物
CN103860463A (zh) * 2014-03-11 2014-06-18 熊妲妮 一种含马来酸茚达特罗的溶液及其吸入喷雾剂
WO2019142214A1 (en) * 2018-01-19 2019-07-25 Cipla Limited Pharmaceutical composition comprising tiotropium for inhalation
WO2020019952A1 (zh) * 2018-07-26 2020-01-30 四川海思科制药有限公司 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用
WO2020105012A1 (en) * 2018-11-22 2020-05-28 Glenmark Specialty S.A. Sterile compositions of indacaterol suitable for nebulization
WO2020141472A1 (en) * 2019-01-03 2020-07-09 Glenmark Specialty S.A. Nebulization composition comprising tiotropium and indacaterol

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023139381A1 (en) * 2022-01-21 2023-07-27 Nanopharm Limited Inhalable formulations
WO2024051683A1 (zh) * 2022-09-05 2024-03-14 立生医药(苏州)有限公司 预防或治疗呼吸系统疾病的吸入用药物组合物

Also Published As

Publication number Publication date
CN115998680A (zh) 2023-04-25
CN113853197B (zh) 2022-08-30
CN113853197A (zh) 2021-12-28
CN115337292A (zh) 2022-11-15
TW202114640A (zh) 2021-04-16

Similar Documents

Publication Publication Date Title
US20150098999A1 (en) Pharmaceutical products and composition comprising specific antiocholinergic agents, beta-2 agonists and corticosteroids
WO2021068961A1 (zh) 一种吸入溶液药物组合物及其制备方法
US20070293460A1 (en) Delivery of a combination therapy for asthma and chronic obstructive pulmonary disease
JP2009502997A (ja) 噴霧投与用の長時間作用型ベータ２−アゴニストを含む医薬製剤
US20070276048A1 (en) Unit dose formulations comprising an inhalable solution of albuterol
EP2319858B1 (en) Aqueous suspensions of ciclesonide for nebulisation
WO2016178019A1 (en) A stable tiotropium nebuliser solution
AU2015261103A1 (en) Combinations of tiotropium bromide, formoterol and budesonide for the treatment of COPD
CN119816309A (zh) 用于治疗中度慢性阻塞性肺病(copd)的恩塞芬汀(rpl-554)
CN108403638A (zh) 一种含有糖皮质激素的无菌混悬型鼻喷剂及其制备方法
WO2020141472A1 (en) Nebulization composition comprising tiotropium and indacaterol
RU2422144C2 (ru) Применение солей тиотропия для лечения тяжелых форм персистирующей астмы
RU2611665C2 (ru) Улучшенный состав суспензии кортикостероида для ингаляционного введения
CN114053216A (zh) 一种吸入用芜地溴铵溶液制剂及其制备方法
WO2020105012A1 (en) Sterile compositions of indacaterol suitable for nebulization
WO2019091082A1 (zh) 一种羧甲司坦雾化吸入用溶液制剂及其制备方法
CN111789827A (zh) 一种硫酸依替米星雾化吸入用制剂及其制备方法
WO2020070599A1 (en) Nebulization composition of mometasone
WO2022166724A1 (zh) 一种福多司坦吸入用溶液制剂及其制备方法和用途
CN117838671A (zh) 一种含维兰特罗的吸入溶液药物组合物及其制备方法
CN118766872A (zh) 一种吸入用格隆溴铵福莫特罗溶液及其制备方法和应用
CN114642656A (zh) 一种吸入用尼达尼布溶液及其制备方法
WO2022231533A1 (en) Process for the preparation of sterilized suspensions for the inhalation by nebulization
CN117064869A (zh) 一种胶囊型吸入粉雾剂及其制备方法
CN114073684A (zh) 三苯乙酸维兰特罗吸入溶液及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20874793

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20874793

Country of ref document: EP

Kind code of ref document: A1